mm^mm
(43)@^^gBB
2002 ^3 ^ 21 a (2 1 .03.2002)
PCX
(10)
WO 02/22587 Al
(51) mmn^^m'i C07D 237/04, 401/04.
237/14, 401/06, 409/04, 491/052, 491/048, 401/14,
405/14, 403/14, 409/14, 417/04, 253/06, A61K 31/501,
31/50. 31/5025. 31/506. 31/53, 31/5377
(21) mmmmm^i
(22) SRSaiSQ:
(25) SRSaiBiOStS:
(26) @iei^6a<D?e:
(30)
j^Bi2000-282636
!^1IH2000-289412
«B12000-342614
0102822.4
0102824.0
PGT/JPOl/08058
2001 ^9^17 B (17.09.2001)
2000 ^9^18 0 (18.09.2000) JP
2000^9^22 0(22.09.2000) JP
2000 ^11^9 0 (09.1 1.2000) JP
2001 *2 « 5 a (05.02.2001 ) GB
2001 *2 5 B (05.02.2001 ) GB
(71) ailiX(3|4@^(ft<±-C(7>mSSlCOt_M:;: X-if
>r (EISA! CO., LTD.) [JP/JP]; T 1 12-8088 S
M&XM^n^^mT m 6#10-^ Tokyo (JP).
(72) mn%;is^xs _
(75) aiK#/aiBiX(*si:ioi>Ta>^>: «^ ©(na-
GATO, Satoshi) [JP/JPJ; T 271-0076 ^mSSi^TfiS
3836-2 Chiba(JP). )\\mVxfSL (KAWANO, Koki) [JP/JP];
=r 305-0045 3S«SO < tf Hi«lB2J-7.201 Ibaraki
(JP). #S^*- aTO, Koichi) [JP/JP]; T270-1 143 ^JS
1-20-1-205 Chiba (JP). *«SS
(NORIMINC, Yoshihiko) [JP/JP]; T305-0061
< rnS^ffI9-7-408 Ibaraki (JP). ±»SH (UENO,
Kohshi) [JP/JP]; T305-0042 3E«SO < tf rfiTltM
668-49 Ibaraki ( JP). ?E BB » (HANADA, Takahisa)
[JP/JP]: T= 305-0003 StWl^O < lirfj62.32-3 Ibaraki
(JP). fflir^tr (AMINO, HIroyuki) [JP/JP]; T 305^821
3E«llO < If m #0 2-24-1-306 Ibaraki (JP). "KM
S (OGO, Makoto) [JP/JP]; T= 305-0035 ^ttl^O < If
m«ift 5-2-36 Ibaraki (JP). SOli*- (HATAKEYAMA,
Shinji) [JP/JP]; X 305-0035 3t«!l0<tfl!it^<t
2-25-9-301 Ibaraki (JP). JtSiE# (UENO, Masataka)
[JP/JP]: =r302-0121 3S«mdbffl SS^^BT^-r *
57-20-6 Ibaraki (JP). Jb — A T > V 3 >
(GROOM, Anthony John) [GB/GB]; SNl 2PX ^ -f
JUhv'-V'— X'!7<>K>=1 -yT^xr — 7
WiJishire (GB). >^ g — T XRlVERS,_Leanne)
[GB/GB]; TN 12 OSE ^> h h>:^'J*>vX-7
/\— XK. X^— — K 22 Kent(GB). X S X -r
U >X (SMITH, Terence) [GB/GB]; CBl 2LE ^ >
ij ^>'?<j V :7;r— ^x hu —
h , V ;J-— Jb KX ^ — ;U 4 Cambridgeshire (GB).
(74) ^SA: "S^ n(FURUYA, Kaoru et al.) ; T
103-0007 mS«**EB*:«^Br2-17-8 ^Br?Efi 1=
JU6K Tokyo ( JP).
(81) (m^)i AE, AG, AL, AM, AT, AU, AZ, BA, BB,
BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK,
DM, DZ, EC. EE, ES, FI, GB, GD, GE, GH, GM, HR, HU,
ID, IL, IN, IS, JP, KE, RG, KP, RR, KZ, LC, LK, LR, LS,
LT, LU. LV, MA, MD, MG. MK. MN, MW, MX, MZ, NO,
NZ, PH, PL, PT, RO. RU, SD, SE. SG. SI, SK, SL, TJ, TM,
TR, TT, TZ, UA, UG, US. UZ, VN, YU, ZA, ZW.
= (54) Title: PYRIDAZINONES AND TRIAZINONES AND MEDICINAL USE THEREOF
s (57) Abstract: Provided are novel compounds exhibiting excellent
inhibitory activities against AMPA receptor and/or kainate recep-
tor, i.e., compounds of the general formula (I), salts thereof, or hy-
drates of both wherein K\ A^ and A' are each independently Cy^
cycloalkyl, Cy^ cycloalkcnyl, a 5- to 14-mcmbered nonoaromatic
( I ) heterocyclic group, a C^-xa aromatic carbocyclic group, or a 5- to
14.membered aromatic heterocyclic group, any of which may be
substituted; Q is O, S, or NH; Z is C or N; X'. and are each
independently a single bond, optionally substituted Ci^ alkylene,
optionally substituted Cj^ alkenylene, optionally substituted Cz^
alkynylene, -NH-, -O-, -NHCO-, -CONH-, -SO0.2-, or the like; R>
and R2 are each independently hydrogen or optionally substituted
C,^ alk-yl, or alternatively R' and R^ may be united in such a way
that CR^-ZR^ forms C=C; and R' is hydrogen, optionally substituted C,^ alk^l. or the like, or alternatively R' may unite with any
atom on tlie ring A' or A' to form together wiUi the atom an optionally substituted Cs^ carbocyclc or an optionally substituted 5- to
8-membered heterocyclc.
QO
IT)
r5
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wo 02/22587 Al
(84) IS^m (Hmj: ARIPO^^ <GH. GM. KE, LS, MW,
MZ, SD, SL, SZ. TZ. UG, ZW), 3.—? i^Tl*^ (AM,
AZ, BY. KG. KZ. MD, RU. TJ. TMX 3 — a y/i^Vf
( AT, BE, CH, CY, DE, DK, ES, FI. FR. GB. GR, IE. IT.
LU, MC. NL. PT, SE. TR), OAPI (BF, BJ, CF, CG.
CI. CM. GA. GN. GQ. GW. ML. MR. NE. SN, TD, TG).
(57) Stdi
(I)
u>m. mm-^nx^^x'hJ:i^C2-67J^^~i^>&^ -nh-. -o-, -nh
CO-, -CONH-, -SOo-2-^ R»43ckZ>'R2ti^tl^*n343tll7Km
*^C = C^?^J*-r5>i^lCR » <hR2<i:e> L^^LTt>J;<, R'«7Km0^> il^
wo 02/22587
PCT/JPOl/08058
N-X5^)W-D-T7./1^^>m (NMDA) a-TS/^S
-t h-a^>^-5-^5F^;V-4-^V^lJ-V-;W":?'Dl^*>^ (AMP A)
;^-.^^>v>^. fsmm^mmmitm (als) . A>^>h>»i^??i^
4. (Stroke) ^mmM. M^^m^ mmmm\z^^^x. mmmm.^^£m^(oif)\^
wo 02/22587
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^ 5 >^ig^3i>^*±# t-T -2) t. (CastiUo, J., Dazalos, A. and Noya,
M., Lancet 1997, 346: 79-83 . NMD A. AM PA.
(Meldrum, B., Brain Res. Reviews, 18, 293, 1993) o T;P">';\'r 0(3:fe V^T
jS-TSn-i' K:J7>/^i^^35i«i^;i^:$'5>®!0#iS#14^i^«e)>5i©^'&-^> ^^^^
^ 5 >^C!)JclCtil ^ /Lii $ -fr ^ .i: ®^^*^$> ^ (Arias, C, Arrieta, I. and Tapia, R.,
J. NeuroscL Res., 1995, 41: 561-566 7^^) . /N--^> V >^tC:43ViTti, L- F-
ACDTKBI'fk'^J&^AMP A^^-j^^fiHi-fbLT (Cha, J.J., et.al., Nexrrosci. Lett.
1991, 132: hh-^^)nmm*&.'^'^^^i^(Om.^ifi^^ (Olney, J.W., et.al., 1990, 108:
269-272, Rosenberg, PA., et.al., Proc Natl. Acad. Sdu USA, 1991, 88: 4865-4869) o
^^^^^ (Smith, T.S., et.al., Neuroreport 1994. 5: 1009-1011) » /N>5^> h
CD^-^*^^^. AlDSa#*«^il1*^^tg^(:a#»c*^*^^4i^*«25S*^
©x>-^D-y^tca5^^^>A5'M. gp 1 2 m.^wmu\^^^ify^^^^^
W.oymL^^'^i^y^'t^ifi (Dreyer, E.B., Eur. J. Neurosci. 1995, 7: 2502-2507,
Uhsijima, H., et.aL, Eur. J. Neurosci. 1995, 7: 1353-1359) . a >@t<^iS:{±i
Slfi*T^^®**gP 1 2 Ofc:J;-5WjS^tt*^^T'5t©^#*^i&-5 (Sindou,
P., et.al., J. NeuroscL 1994, 126: 133-137, Muller, W.E.G., et.aL, Eur. J.
Pharmacol. Molec. Pharmacol 1992, 226: 209-214, Lipton, S A., Neurology 1992,
42: 1403-1405) o T V )V^-'<^^m^mz.^\^'C\t,. ^^m^^^^-^^^^-^
^ (Hardin-Pouzet, H., Glia. 1997, 20: 79-85) . :t U -:/^S/J^Bi^tt^^ix mz
;>{^^y-j ym^-^m-t^ z. iii!)t$>^mB-v. AMP As#<2^^«fieT^-y-:^:3--
h GluR2 0D^#:7&S.Effl$nT:fe D (Gahring, L.C., Neurology 1997, 48: 494-
500) . :tO~':^W\^m^ii^tAMFA^^i^i:(Ommi>^^^^^'^^^^''
wo 02/22587 PCT/JPOl/08058
AMP Ag##o5 c a ^ ^mm^mi^ v.mvf^mz. vxmzm o m t <om^*^
db^ (Brusa,R., Science 1995. 270: 1677-1680) . ^Omz. NBQX (2,3->^
t K a=^2^- 6 h P - 7 -7.;V:7 T )V-^>^A^^^'^^ 'J Sheardown at al..
Science. 247, 571. .1990) ^fe^DJ&irfSAMP A^^#ia^^k^^*^^
<ki;fm5g«f^ffi ?rWr^ t (Dm^-^ (J. Pliarmacol. Esp. Ther., 260, 742, 1992.
Phai-macoLBiochem. Behavior, 1998.60:119-124) . ||«^a«4>«*^
^i:AMPAS^^/'^'1':=^>^^^^<^^<^^^'^^^''^'^^^^^'^^
Pharmacol. Ex^. Ther.. 280, 894-904, 1997. Neuroscience Letters, 268: 127-130.
1999) .
muw&mm.of^m\z\-s.. mm^¥?mmMmn^mmzifi\.iiuigi^^ ^^rmm
ibi^mx$>^tmw-r^t}iib^x^^o tDt)VtAMPAS^^*-^:^-i'->
^^^i^^\±ci^fr^^muDA^^mzi§mi^m^^-r^mm(Dmmmm
^^nxvi^s. mpiit^ woo 0/0 is? 6\zu. ^)u^^>^^aufa^^
V-ZN-lx-S^-I^P. ^) . Marchifeva-Bignami^.
^.L^i^mmmH^mm. n^Mmm0ii iy'^dyi^m) . a*d^, hi vi4axa/'?->
©«^*^feSo AMPAg^#- *-f->^s#{^icffi»f^ffl^*-r^^t;^'^t^
(1)
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NH2
(3) ^om. W09 4/2 5 4 6 9, WO 9 6/1 0 0 2 B^^XSUS 5 3 5 6
m^it^m\zm-r^mm^^^>^rc. W095/01357, W097/281
35, wo 97/2 8163. W0 9 7/'4 3 27 6. WO 97/3487 8, W
O 9 8/3 8173, EP80219 5^^mB 1 9 6 4 3 0 3 7#^lffi^}C:fe
4
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0 l43j;rXUS 5 3 5 6 9 0 2m\Z. =^1^-U >>'^>#^^?ft""rS^°^AM
TA^mi^m.^it^m^z^T^m.^fi^^^o wo 9 5/0 1 3 5 7, woe 7/2
8 13 5, W0 9 7/'2 8 1 63, WO 97/4 3276, WO 97/3 48 7 8,
WO 98/38173, EP80 2 19 S^^ZSbB 1 9 6 4 3 0 3 7mz. t^W.
-^«)AMPAS^#:K#'fb-a-#3{wMi-^^^5?'^*ab^. WO 9 7/1 7 9 7 0 t::, A
^-f^ffl&wr^tfu Y=^Ti^>wmw\zwt^m.^i3^^^o woo 0/2 7351
ICtt, NMD Af^fflJi!^:fe AM P AMf^^ tcS"^ < ^^M^^m ^^t*
'g-tfU^>^/>^#-(*:(-M"r'g>^^*«*'S» woo 0/4 7 5 6 7 iCtt, #^NMD
^n-^*n3£ALbX7KS, tKMS, Aoy>, v-Ty, -bn, i£^TJi/=¥;K (-^
truyv^yMb'&^feti^T:- «rj^OT09 9/1 o 3 3 i, wo9 9/1
0 3 3 2:feJ;tXWO0 0/2 4 7 1 9\Z\t. ^yifWt^l^^i — if 2ffil§^^tU
wo 02/22587
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-r^m^iJ^^^o ^fc. wo 9 9/2 5 6 9 7, 9 9/44 9 9 543ctOTO0 0
/5 040 8ic«, ^^-p-f^^i ^m±nmMtvr<D}iv y-yy >mmi^
lc:||-r5^^*^2feS. -ei^T. woo 0/0 9 4 8 SK^t. m^^^Mm^ifFM^^
T-s tr u js^v'/ >^^#:fcii-r§^€*«*s. $ e> wo s 7 / o 7 1 o 4 , e
P08604 35. EP0963978, wo 0 0/34249, US 61072
5 0, !^mW-5-2 5 1 6 4-^^^, DE4 4 2 3 9 3 4^JC'foJftmffif^t bX©
(om.^ifih^^(00. AMPAS##/;*J^->mS^^^:®^3St-'^^^"Ciaife7&«
75:<^<^6.nTVi75:V^o 2. 4:feJ:r^6^tw^4^§m»^W-rS t!Ui5^5^>- 3
-:t>^^#:*5j;tXl. 2. 4 - b U 7>^>- 3 -:t>^J^«:<i:AMP Ag##:/
M P Ag##:43 J^lJ^/^fett^-f L/^tii-r t
wo 02/22587 PCT/JPOl/08058
1^>S. g^$nTViTt)J:ViC2-6:5''>^^-l^>*> -NH-, -0-. -N (R
4) CO-, -CON (R^) -N (R«) CH2-, -CH2N (R^) -> -
CH2CO-, -COCH2-, -N (R8) SOo-2-> -SO0-2N (R")
-CH2SOo-2-^ -SO0-2CH2-, -CH2O-. -OCH2-, -N (R^
0) CON (R^O -N (R^2) CS-N (R^') -*fc«-So-2- C^^-
R^ R^ R6. R^ r«. r«. R^^ R'^ R^^^^xSR^m^n^n^^
tTK^M^. Ci_eT;v4^JV«fc«Ci_6T;i/3^->'*S:^-r. ] R^43j;r;J
Rm^ri'ennmzim^^^ em$tiTViT=bJ;i/iCi_6T;v^;v», m^^n
T v^T t> .k c 2 - 6 ;w^r jzjws^ feti^^^ tiT v^T i c 2 - 6 7
Sr^-r*^ cR2-zR^*«c=c-e«t>$n^j^^^^-«^^^?^^"r
] . Rn^TK^JM^, s^^nTv^Tfei^iCi-eT.ip^^vs, emsnx
t> J: c 2 - 6 tiT t^T ^ c 2 - 6 J^^--'^*^
-en^'ne^$nTViTfej;ViC5_8m7K*^^;^cJiS^^nTViTt><tvi5 72;
MSfi^^^^&J^fiKbT'biVi [fcfcU, (1)Z*^NT. x2:fe^r;x37&^m^
x'^^^S-^-e, A^5&«o, p->?p<5^;i'7ai-;i/Si?, a^t&^o-p^^;!'^^::^;!'
«T\ R-D. A 3*^^:7 x-;i/ST$>^J^^, (3)Zd«N-^, X^ X^^J^t/t
X^Hj^^^'^X. A*y&^o-^5";i':7xi::;vaT> A2:6^*p-p^ b^->:7x-;VS"^.
A35&^7:il-;l.S-e^^^^^ R2i5d:UCR3(7)e>^'>7^< tt>i^t**^^
#l«l^*^nSo (W^«l3iZR^-CR^*«C = CT-, R3:«)t7K^M^T?x X»*«--
7
wo 02/22587
PCT/JPOl/08058
J:tN'A3:^>^-7a:-;i.S-eab^«^, (3)HP:$3-^3gZR»-CR2*sc = CT?. R^***
(4)gB4^^5gZR^-CR2*^C = CT:\ R^^^^^'TK^I^^-e. X\ X^cfeitK
X33&t#i^-&T. Ai:feJ:DfA2*t7x-;i/S-e, ac>. A3*tp- h;w;i'S^fctt
t.=^,>7a:-;i'ST^^«^^ (5)SP^«3gZRi-CR235«C = C"r> R?*^
N-^;i'7:tU-;P»Tfe^^^, (6)BK^«3gZR^-CR2:«>5C = C-C. R3;«)t7K
^M^T?, XK X^&^UX^iimm'^-C'^ A^5&^2. 4. 6-hUp^5^JW:7x-;i/
ST?, A27&s:7x-;i^^> B.':?^ A»*«3. 4 ->^i^nD:7aL-;i'S-i?fe (7)
Zd«CT, RK R^^^ZJ^R^i>^y^mm=I-'V. X^ X2:feJ:TJtx3d^^^^T?, J.
■D^ AK A2:feJ;t;CA35&«7a:-;i'«T^«^^> (8)Z*«C"l?, R^ R^^J^t/^R
37557K«m^T'> X^ X^^oJ^D^X^^WM-erl?, Ai:feir)fA25&i7 3:n;i/«T?,
3_Pt |.:^i>-4-3— H7x— 3-i7na-4-p^h^->:7x::i;i'«, 9
-7>hy-t=l)Vm. 3-:/0^-4-^ h:^^>>7ai— ;i'«fe«4-p^5';i/-3
-H-K7ac-;l'S-??S^J^-&. (9)Z*«C-e, Ri, R2^J;tKR3*«zK^M^-e,
x^ x^cfe^ofx^T&ims^^-e, a^*«3. 5-v^>^^;i'- iH-tr^V-;i'- 1-
p-i7DD:7x:^;vS> p-^ h4^->:7xn;^*, p-h;w;^S, 3,
uny3L:z}V&. 2. 4-v^5^;i<'7x;i;WS*7t«3 -p^9^;k-4-i^po:7x
-jWS-Z?*'?.*^, (10)Z*iCT% R^ R243iJKR3;5^7KmM^t?, X^ X^cfe
j;ijcx33{>«m^-&'e, Ai*«2. 4--:^^^;w:7x:=i;i^*T?, A2:6t:7x-;vst?,
A35&57x-;i/a, p-h;i/-i-;i/S, 3, 4-V^nuyaL-.)V^. 2. 4
8
wo 02/22587
PCT/JPOl/08058
->';^5^;i/-7xn;vasfci*4 3 -7*o^::7x-;wST'fe^«'&. (ii)
nR^7!)^7iimm^X% XK X^^^UX'Uf^mi^^-C^ A^ffi2, 4.
x-;w«^c:«2, 4-i?-ho7x-;i'STa5^:^-&> (i3)z*^c-e. R^ r^
y^^zDV&'V. A2*«7xnJV^"T?. A3*«p-i?:7ai-;i'». 3, 4->>^
uuy 3L:z)V^mt\t 3 - d 7 (14) Z 3&«C
R^ R243J:t^R«*^^7KmM^T?. X2*J:tKX^7&W^.^"T?, A2*«:7x
a3jJi^*p-:/o^::7x^;w*t?, fio. a^t&^p- h;w;ViS>
;i':7x-;p«fci^p-'rv:7'Df;v:7xn;i^»T^^^^> (i5)z*^c-i?, R^
R2:j3J:U:R3*l7Kmil^-tr. X^ X^^^ZSX'ti^^^m^X% A^t^y :i^:^)i'&X.
A^:feJ:r)fA35&ip->^ h;^«^s^:7x-;i'S^:fc«3. 4->^>^^;i':7x::i;p»
(16)Z75«CT-, R^ R2:feJ;UJR'*^7KPfeM^-^. X», X2:feJ:UCX^
A^)5«p-h;K;W»-^> A3*«7x-;i.«T?. A^d^p-tJ^D
d:7x^;W»TS^^^^ (17)Z*^*C-t:. R^ R243a:OT^*^*^i^^-e> x^
X^iJj^I/tX^T&s^^^T^ A i:fe^Z>*A 3:^5:7 x::i;W«T% A 2 ;e?n - 5^;^
lf-^U5?>-4— r;i'*T-S.^4i€r. (18)Z5&SCT% R^ R243.fcI^'R^*^^mM
^T, X^ X243.i:lXX3*^^^^-C. Ai*^2. 4. 6 (IH. 3H. 5H) - 1!
U5i?>>»J:t>-5— f;i/»T, A27!)«7x:^;i'ST?, ^O, A'*«3 ->^5^;i'-
4-^7DD7x-;l.»T$»S^^. (19)Z>&«CT% Ri, R2^3<ttKR3dt7K^M^
-t:\ X^ X2^J:t;x375^'m^^T\ Ai^J;tJ?A3;&t2. 4 -5>^^;w:7xr:;i.s
-e. Jg.O. A2j5>i2. 4-i^- bn:7x-;i-STS^Jl^. (20)Z7bmTr, X^d^-
R2i5j;i;JR3*^*iS®^T. X2i3<J;DtX37:>W^^-e. A^ A2
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9
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AMP AS^^^* J:tJC/'^fc«:!t7-<n>M^^#:^$*n:f^^ §^-r d t SBffib, *
i-Tit)-^. *^Bj«, (1) MiB^ (I) T^*D$ns{b^'^'bb<«-e©m^
feJi^n6©7Kfn#j. (2) BtfIB (1) l;i43ViTA». A2*3J:thV^fet3:A37&i^
^©ig*fctt-en6©7K?0#>, (3) tSf?3 (1) \Z:^\^^XAK A^:^^Z^A^:^^^
i^, (4) WlB (1) (C*3ViTA\ A^:$i^ZfA^i)^^n^nn^L\Z. ^ti^n®
tfnUi^n;i'S> H^Ui^r:i;WS. k!^^>?::^;i/S^fct*^;i/:7:t U::l;^
^-Ir^-5'^k'&i^feU< «^0^Sfc«-^n^07K?Pi^> (5) Buia (1) t^fevix
wo 02A22587
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7;i.^-W'>»t)b<aC2_6T;i/^-V'>S.(c)-NH-,(d)-0->(e)-N(R
^) CO-, (f)-C.ON (R5) (g)-N (R«) (h)-CH2N CR')
(O-CHaCO-, 0*)-COCH2-. (k)-N (R«) SOo-z"^ ©-SOo-
2N (R«) (m)-CH2SOo-2-- (n)-SOo-2CH2-^ (o)-CH20-',
(p)-OCH2-> (q)-N (R^°) CON (R^^) (r)-N (R^^) CS-N (R
-^fc«(s)-.So-2- K-l^^ I^'^
Rii, Ri2:fei;t;R»3ti:^n^nfi?I3 (1) |3m©^«i:M»^^"^» 3
-c^n^nmm^ nrviT j: c 3- s d c 3. « ->i^ a 7)i^^=^
T^/m. {0 2-67)1^^=^)1^^ Tsys. N-Cx_67;p=^^;i'-N-C2-6T
;i/y-;wTays, N-Ci_6T;i'4^;w-N-C2-6T;i'^-;wT5ys. N-C2
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24
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26
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27
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1 -^D^x;i/:t-^->»^ 2-yD^x;U:t4^i^*. -rVT^O^-jP^^^v-S.
_^5Lji,_2-:/D/>^-;w:^:^>'». 3-^5^;^-2-y□^x;^^=^^>»^ 1-
yT-XjV^^^-v-S. 2-:/5^iiJl':e^'>S, 3->^^-;l/:t^->S> l-^>y^=-
l-^^-t=.)l:t=¥iym. I, 3-^=^^1J->>'xr:;i^:^^'>S> 1.
5>^ny5^;u», i^^o^>^;i/*. >'5^p^^->;i'»> n-^:;^^;!/*. v'^
33
wo 02/22587
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>:^e;x>-i — 1, 3 ->'^D^>^'i?x>- 2 — r;K i, z-y-^u
^y^i^ji>- 5-^)v. ->^a^^'fe>- 1 2^i7D^j^-fe>- 3 — r;K
~>ij7n^^-fe>-4 — f;K 1, 3 -i^i'o^^-9-^x>- 1 — r;K 1. 3-5/
i^D^:^-ii->'x>- 2 -'I'JK 1, 3 ->'i^o^^it>^x>- 5 — r;K 1, 4-
->i^n^^1J-v^x>-3— I'M 1. 4-->^n^^-9-i^x>- 1 — r;K ->il7a
— z^^u^-:f5^>-s — r;p. ->^^D^y7^>-4— i';k
^n^T^T^v-s— r;k 1, 3-v'^D^y5^>-2-^;p, 1. 3->>^^o^
i5'e^x>-6— r;w, 1. 4-->i^a^::^i$'5^x>- 3 — r;K i. 4-yi7uy\
:/^e?x>- 2 -<;k 1, 4-5/i7a^^^v?x>- 1 — ov. 1, A-yi7u
•^zf^'^:^>-&-^ 1. 3. 5 -~>^D^yi$' hux>- 3 — r;p. 1. 3.
5_,^/7P^v:/^hUx>-2— r;^. i. 3. 5->'i7n^:/^>'jx>- 1 -
-f;k 1. 3, 5-->i7o^:/^ hUx>-7— f;K v'^D:ti7 5=->- 1 — f ;K
y'i7U^i7T'>-3 — r;k ->;J?o:4-i7 5">-4— f;K i^5^n:^^^>-5 — T
;K 1. 3-~>i^O:r^7^>?X>- 2 — r;^, 1, 3-->tJ7D:^i^^>'X>- 1 -
1. 3-->^0:t-iJ7 37 5^X>-5— f;!/, 1. 3 - a:^iJ7 i5'i^X>- 6
— r;K 1. 4-->^0:t^^S^X>-3-'f;k l, 4-~>iJ7n:ti7:$'>?X>-
2_^;K 1, 4-->^n:^-^:$'>»X>-l— r;K 1. 4-S^i^ n:ri7r$^S?X>
-6-<;K 1. 4:-y!7U-^{7^i^:SL>-7 1, 5-v^^a^^^>^x
^_3_^;K 1. 5-">t^D:;e-^r$'v'X>-2-'l';K 1. 3, S-i^^'O:^^
34
wo 02/22587
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hUx>-3— r;K 1, 3, 5~zy^U:t^i^ h^J^y- 2 -^)1. 1. 3.
5->'r^O:t^:$' h UX>- 1 — ( JV. 1. 3 . 5 - '>;J7 0;^-^^ h ij x>- 7 -
-iJV. 1, 3. 6.-$>e7D:t:5't$' hUx>-2— r;i/. 1. 3. 6->'i7 0:^i7^
hux>-i— r;K 1, 3. 6->'i^a::d-^^ hUx>-5— r;K l, 3. 6
>?fcHotf^n;i/S. -r^rJ'VJ^;!'*. :t^r-y-V^U::::;vm. ^d^^tf&nSo
m^mf^t. :7aix;i.^. -r>7'-ji'S. i—^y^Ji^M^ 2-i-y^)i'm. t
i?;!/^!/^;!/*, :7x±i/x;v», :7x:^>hU— T>h^-fex;i/«. v-i?
35
wo 02/22587
PCT/JPOl/08058
DU^l'S^ }dV^i^=-)\^&^ tfU5>?~;V«. tf^>^:::;i'S, hUT
±y^^ji^=^}m> ^y^^'JJi^&^ ^i-^/^j-jm. -»yu-;i/»>
Ttt5^7VU;V«. -iV^TVVJV^. ^>^/^7V0)m^ ^>X^7-J7^/')
wo 02/22587
PCT/JPOl/08058
B^mi^mMm^mr. A. ak A^-^^^zSA^z^n^Bmumm^zfm^n
l?DU;i-«, IfUS^JV*. lfU^-:^::^>>l'S, t!U5S^-;l.S, t!7i?:^;i-».
-i'5^vtfu>^;vs. >/^7d^>5^;vS> ->^n's:^->;i'S.
^D-s:^-t-;u»> T^*"7>^;p». ifDUi>:z;i.», i^-<us^
37
wo 02/22587
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nmfsimtvxu. -Nx-friTKma. 5":t-;i^s> Aa'^r•>I^^^ -hu;i/Xv-H
C2-6T;w^ii;v». Ci_6Z>=i4^s^S. C2_6T;i/y-;i/^^->
C2_6 7;i'^-;i-:=^-=^^">S> Ci_6T;1'=^;1'5^:^»v C2_6TJWy:^;V5^:^S.
i t e r t n-^>5^;US, i -^>^
;u:/otf;i/«. 2 -x5^;i/:/pf;i/«> i-p^^;i.-2-x^;i'yDH;i'S. 1-
t:x;PS. T'J -Jl'S^ 1 -yn^x;P^*> < y yo^x;!/*. 1 -y7^>- 1 -
38
wo 02/22587
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T'b<fcVix^^;i'^>. i-7°oif-;vS. 2->^oif-;VS. ^>9-
jian^ i<@isiLJb©s*«fei'f ens.
i -7-o#^">S, sec - :/n7l^^->», n-^ h^->*. i s o -Zfh^^^m.
^-^m^ sec-^>h^->», t e r t -^>h^->S^ n-^=^V=^~>^. i
so--s^v^i^m. I. 2— :?;A5^;p:/o^=^->»^ 2 -x5^;i':/n#^~>S.
j^_^^;^_2-x5^;p:/D3l?^>'S. i-x5^;i'-2->^^;w::^a7it:^->»> 1.
1, 2-hu^^;vya>J^=^->S^ 1. 1. 2-hUp^5";i'::^D#^>'S. 1. 1
-i^)/i^)v:fh^z^m. 2, 2-^^^^;i':/b^^>*> 2 -x5^;i':/h^->S> 1.
3_c;pC5^;i,:7>^->S. 2-p^5^Jl'^>h=^->*^ 3-^5^;i-^>b^'>«' ^
39
wo 02/22587
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- 1 — r 1 -y'y^>- 2 — <)V=^-tm. 1 3 — <
2--:f7->-i — r;w^^*^ 2-::/^>-2 — DV^-t^. . J^t/^. Cz-e
^>5^::::;W^:r». ^^^->:z;i/5^:^-S. tf^^M
©WCD'CSJiiLT^, Ci_6T;i^^;i^a, C2-eyJ^^=-}^^> C a-gTJ!/^— JUS^
TayS. n-Ci_6t;i/^;1'-n-C2-6 5';1'^::^;i^7^/s^ n-Ci_6T>
wo 02/22587
PCT/JPOl/08058
4^;!.- N - C 2 _ 6 7}l^=-)lT 5 y N - C 2 _ 6 7)1^=^)1^- N - C 2 - e T^^"^
2_^7)V^:^)VX)\^^:^}l'M. C i_6T;i^=¥;i/*;W3j^->'V^' C2-6 7;i/er-;V:&
M^n. mc^.^7)i'^jvm. c^-e^^^^-^^^- c2_6t;i/^-;ws.
Ci_67;i^^^v?5JJi'3i?-;v». C2_6TJi/er-;i':^3;V3t?-;i/S:feJ;t;^C2_
\Z$>\,i^t. n-:/ot!;V'T5 7»> iso-
yDtf;P7ay», n-y^^JPT-S/S. i s o-y'^Jl^75,y^. tert-y
5^;i/75yS. n--^>5^Jl/TayS. i s o-^>^)V7S.y&. :^:t-^>^;i/
\f}V7^JM. l-X.^}V-2-?^^)V^n\^)V7^/&^ 1. 1. 2-bU^5^
2, 2->'^5^;i/:/^;i'TsyS. 2-xg^;^:7*5=•
;^7ay». 1. 3->^p^5^;v:/^-'^75yS. 2-^^}i^^>^)V7s.j&. 3
N. N-i^ (n-^at°;i/) Ta7», N. N-v' (i-yPtfJW TSy«.
N. N->^ (n-:/5^;W T^/a. N. N-S^ ii-'^^M TS/*. N, N
-5; (t e T t-y'^JV) 7S/». N. N-i^ (n— ^>^;W T5y», N,
N-i? (i-^>5^jW) N. (^^:4-^>5^;W 75^*. N. N
41
wo 02/22587
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N-x5^;i/-N- (n-::?^Dtf;i/) rays. n-^5^;w-n- ( i -:;^Pt°;i/)
T^/S, tf-ji^ya^S. TU)VTs.y&. (i-yo^-;i/) ts/*. -fv
}V) 73jm. (1 -:/5^>-3— f;i/) T3.j^. (2-:/^>- 1 —fjw t
syK. (2-:7*5=->-2— r;p) T^y»> n, N-i?if:i;i/Tsy«, n. n
\f.-)V73Jm. 2--^U\^=.}V7S,jm. f=^=.)V73/^. ^>^ZL}V73y
^^i^-)V75./m. N. N-->x^x;i.TS/a. N, N- (l-:;^Dt!::i
jv) /S. N. N- (2-yu\f=L)v) 75.ym. N. N- v^:/5^x;wy5 /
N. \^-z^^>^-)i^7s.y&. N, N->'^^v--;wy5 7». tna^s^
3_tHD:^5^ - n - yn :^^)V:^)V:^=^)V75.ym. JL'^)U7s)V^=-}]^
7s.y&> n-:/pe;P7.;P3fcn;PT5ys^ i s o-yatr;i/;^;i/sK—
n-:;^5^;P7.;w^x;vT5/S. t e r t -:;^5^;i'7.;i'*x;vTS7S, b-x
;VT$y*^ i s o-^>5^x;^7.;i'*x;uT5/S> x5^x;i/x;V3}Nri;V'T$y
x;i/«j , r«^s^WbTViT'bJ;v^C2_6T;i'yx;i'7.;i/7^xjwsj ^^zf
42
wo 02/22587
PCT/JPOl/08058
(omfSimt:$>i>f^t. ^5^;i/x;i/>i^-;i'S. n-7'at!;i'
i s o-:^atf;i/7.;v^-;i'S> n-:/5^JP7.;W'J^-;US. t e r
t -:f^}V7.)U^::^)vm^ iso-y'
so'-fu JV-y < n - f^JV7.)Vy ^ t e r t -
)V7.)vy ^ =.)V&> i so -^yv'-)V7.)vy ^ ::l)V^^ x^-;w;^;V7^
i:iUi?;wx5^;i/S. 5^xx;i.;A5^;p», 5^xx;i'X5^;i/S, W
^.y^}V:fu\i)v^^i^m. mt^ mm ^-\y-u7^)'-)V7)\^^)V
y'j;i';'^5^;v^^->»^ :7;u:7<j;i':^^e^». 9^xx;^^5^;^:^-^~>»^ 5^t^/u
n-:/oH;i/*. i s o-7°Dti";i/», n-'^^)vms iso-':r^)vm. t
e r t-y^;i-*. n--^>g^;ua, i s o--^>5^;VS. n-
p^^v-*. i s o-yP3!?:;|-->«> s e c-:/a3}?^5^«' n--:rv^z^m> i
43
wo 02/22587
PCT/JP01/08p58
i s o-'^>h^>'S. sec-^>h^->»^ t e r t-^>h4^S/S, n
(mti~>^^°:^Di^>'^»^ e/iJ7Dy^;i.S> ->>^D-^>5^;va6, ->^7d^=^^->;u
M 1 4 M^#4^^i*^i^*J r 5 7!;M l 4 *^^^Si^^*^^3lJ . ""c
ifpU5?-;i/S, tfD'j-;vs. tr^Ui^-;i'S, tr-<^>^-;i'*. -i-sr^^^/u-
U;WS. tfU5^;V»> tfU:5^i^-;i-»^ HU^i^-^l-*^ tf^>^:^;P». tf^VU
x5^;PS, n-ynH;vS. i-:/nif;v«, n-'f^}V&. i-zf^
44
wo 02/22587
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^^->S. s e c-:7>:^->S. t e r t-::^h=^->«> n-^>h=^->S. i
> h=^^->^^ sec h^^v'S^ t e r t n— ^4^V^~>S>
Jl©«^©RH3:N(^^>t*^^^ (lone pair) ^^To
_gT;V4--U>«, -NH-, -0-> -N (R^) CO-. -CON (R^)
-N (R«) CH2-. -CHgN (RO -CHgCO-. -COCHj-. -
N (R«) SOo-2-^ -SO0-2N (R") -> -CH2SO0-2-V-SO0-2C
-CH2O-, -OCH2-, -N (R^°) CON (R^M -N (R^
2) CS-N (R^') -*fc«-SOo_2-^^"^- H5IB^4»®R^^ R^
R^ R«. R^ R^°. R''> Ri2:fej;tKRins^ti^nafi3:t-:?K^M^^ Ci_
X5^;i/», n-:/ntf;i'», i -^Dt!;i.s, n-:;^9^;ws. ter
t-:/^)vmii^^ rCi_6T;i'n^s>*J t b xh^^v-S. n-
ya#:^$/S. i -T^'P^^^v'*. n-7*h=¥v'S. t e r t -:/5^;i':^^~>«%
75:*5. iC4'®-SOo-2-'tii. ^^mibT©S*40, l^fe«2<@®0^%
■r-5c:t^jti*b. ^^regjcms-rsa:, -s-, -so-^fc^-soa-x^
45
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=.u>M} tit. -en^nWBB rci_6T;p=^;i'«j . rc^.^7)\^^-)V&i ^
j:zj^ rc2_6T;v=^^-;wsj \zMj^-r^m^m^miy> tt^mtsimiivxit-.cH^
- (CH2) 2-. -CH (CH3) - (CH2) 3-> -CH (CH3) -
CH2-. -CH2CH (CH3) -CH=CH-^ -CH=CHCH2-, -C
H2CH=CH-, -C (CH3) =CH-, -CH=C (CH3) -C = C-.
-CSCCH2-. -cHgCsc-. ^afiM^n. j;os^jS:fe0ytbTtt-cH
2-, - (CH2) 2-^ - (CH2) 3-' -CH=CH-. -CH=CHCH2-.
-CH2CH=CH-. -C = C-> -CSCCH2-. -CH2C = C-. ^Tfe
rg^^tiTViTfecfcViCi_3T;i'=^^>*j - rM^$nx^iTfe«kViC2-
gT'jl.^rnl/^Sj *5J:Z^ reM$nTViT'bJ;V^C2_3T;i'=^-l/>Sj I3:fefrt^
'bj:ViCi_3T;i'^i^>Sj . rgjfe$nxuxt>J;viC2-3T;u<^-^>«j ^
ir/ rg^$nxvixfeJ:vVc2-3 7''i''^-i^>'*J id^i-tsSfiSJ^Siuxj*,
-CH2-> -CH (OH) -CH (CN) -CH2CH2-X -CH (O
H) CH2-. -CH (CN) CH2-. -CH2CH (OH) -CH2CH (C
N) -CH=CH-. -CH=CHCH2-. -CH=CHCH (OH) -.
-CH=CHCH (CN) -CH (OH) CH=CH-. -CH (CN) CH
= CH-. -c=c-. mifi^f^n^o
XK x^^^x^x^z^n^iffmi^^^i^x\-i. m^^. -CH2-. -CH (O
H) -CH (CN) -CH2CH2-. -CH (OH) CH2-. -CH (C
N) CH2-. -CH2CH (OH) -CH2CH (CN) -CH=CH-.
-CH=CHCH2-. -CH=CHCH (OH) -CH=CHCH (CN)
-CH (OH) CH=CH-. -CH (CN) CH=CH-. -C = C-. -
NHCONH-*«2feVf e.n^. J:0»®J&:»tt. m^^^ -CHa-^ -CH (O
H) -X -CH (CN) -CH2CH2-. -CH (OH) CHg-. -CH (C
wo 02/22587
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N) -CH2CH (OH) -/-CH2CH (CN) -CH=CH-.
-C = C--^^ KfC|ifjg:^j;StbT«m^^. -CH (OH) -T%
R 1 - c R 2 -^^ 0 c= c'T?^$n^a3g*?^sK-r^«k'5 ICR
^ t R 2 £ 3 UT 'b J; '/^o ^fc. (2) Z ;5>^*N (Z) R ^ (lone pair)
m$tlTV^T%J:V^J ■e^Jx.t^7K^S. -hU;V». Andr>M
^ (^JAti^-y^M^. m^M^. 3'j7^m^^) . ::iha«>
2_6 7-'^'^-''^*-' ^^^^ ^n^tiwiB^iitiii«^^^"^o
47
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itftx^j^i^^-^T?, A^*^o->^5^;i/:7xn;i/»T', A^^^p-p^ h^^->:7ai— ;^
rs^$ nx % <t c , _ e > r®ife$ nx v^t t>i c 2- e t
A^ A^cfeitXA^OfiimSO^^t-I^CX^-S).
R^T&t rA^±*fcl*A3±©Vi-rn*^®l^^tM'&bX^^l^^i:i:'btCJ
48
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1^'
-0-. -OCH,-, -CH2O-, -SO0-2-- -SCHg-, -CH2
-SOCH2-> -CH2SO-. -SO2CH2-. -CH2SO2-. -N
75M 1 4 em^ nx =b ck c 6 - 1 45f #t^^<b7Km^^* ^
('^fF5i75:^««. D^fc«E*«-CH2-^ - (CH2) 2-> -0-. -S-. -
so-, -SO2-. -NH-. -O-CHz-^ -CH2-O-, -S-CH2-.
-CH2-S-. -SO-CH2-, -CH2-SO-. -SOg-CHa-^fe^*-
cH2-so2-©^^T-feo^ m%nmumm\t. D^fe«Ed^*-cH2-. -o
-fb-^r^j (I) tc:43ViT. R35{)iAi±*fcJiA3_h®Vi-rn*^®M^^:^'&L,"^^
49
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c^4", 5iAi»> A2»:fej:z/A3*j«n^na6Sc-en^nsm$nTViTt>i
6-14
50
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(i-i) ^rc\t am xmt>-^n^^^'^\t. ^
(iii) (ii)'
cis:^'. xK x^ x^ A^ A^ A^ a^^ A^'^^s^t^^B^emcR
51
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h;vx>, @lF^#Ta5§o -^ffi-r^M^t K^>^>m^-f2^«> m^M^s^.
ig^T*s^b^% (1-2) s^ctt (m-1) ) tt, ^
52
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53
WP 02/22587
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Ar-L) i:(DK7Jiv'^>Km^h\i<E>n^o s.m^mtm\zmM^ni3i\f^-^i.
r-B (OH) 2) ^m&(ow^-fm<t^m^m^^xti^y':r'J>-^-^'&^:&mti^^
fsi\,my)iz^^^xmzmM-^n-f3:^^ti^> $?5i{c«hux5^;i/Ts>, t^u>^>^ ^
g^m^. i?-HzL k Ho:^^y-lf7> [ (N, N, N' . N' -T-h'^^^JVJL
Km^mm'&-rnimmm^^^nmmMr^^<Dx$>n\mizwt^^nis:^^f}^. w
comm. iR^©iRi±^«fcom»35:M^*^#6»n^o
54
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R2 r3 oh
^^^^^^
o
Ar' -CHO
(vi)
(1-3)
iCf. A^, A^; R2:feJ;t;^R^«M^5tfelCl^^«^^b. Ar'
MIBSC: (1-3) -e^fe$ns<b'&ife«.^(vi)o*n^t^u^s?y>M^®tfU
2^%0j(c:;&i3&^SMI2^ (I) x^^ns^k^i^JccJsViX. Z36«NXfeSTS^ (i-
4) Tgt)$n^'^k'&2^^^^ ^
55
wo 02/22587
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3 r2r3
X3 ^ "v3 ^ Ti '^3
o o ^
NH
(vii) (viii) . a* |
(ii) (ix)
A
3 r2r3 R^R^
(x) a2 (xi) A'
2
A3 R2r3
a1— X^-L'
or
Ar-L'
or
Ar-B(OH>2
N
xK x\ x\ A^ AK A\ R''^xzj^R^\'imtmmizmMm^^
(1-4) T?^$n-5-fb^tJ«> a-AO^ b >mmi^(yu)^ a-7>^^^ ^
wo 02/22587
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57
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imm^^(D^ Ar-B (OH) 2) :©S©#«ET, ^{b'&'^^fflVifc
[ (N, N. N'. N'-5=-h^P^5^;i^xg^l/>-^^S» ^ <II) ]
58
wo 02/22587
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X
(vii) (xii) (xiii)
a3 R'^R' «1 «3 R2r3
I.
I,
A*
(ii) (xiv) (1-4)
X^, A^ A^ R3i3j;tKL'«MfB^«t::il!««
(vii)tT$>l§^#^(xii)<7)5^^SfCi:fcJ;0^3tr^. hUx5^;i/T5>
59
wo 02/22587
PCT/JPOl/08058
2^^§9-fb-&#J (I.4) /&t4it-r^fcae)CD]gtog C4'FBWxiv)/&^6. (1-4)
I@D rh»J7>^/>U>i^'fbJ lc::feViT, $f3S75:-KJ^^#«. (xiv)^.
A 3 R2r3
X
(xiii)
A?-X2— L*
or
Ar-L*
or
Ar-B(0H)2
NH2NHCO2R'
R2r3
V^^^^^X^
H
(XV)
a3 R2r3
(1-4)
^fp. XK XK XK A.K A\ A\ R^ L •:feJ;l^A r JittrlS^ftlC
60
wo 02/22587
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NHCO2R' ) cD;i3S^j^j;S(wckD^^^n§hU7>^y >^«mxv)Jc. 2&:mm
(xm)tt:H^e?y3t7;W3h'>mxXx;Pm NH2NHCO2R' ) <^SS
mm\-i^ mmmn. MM^i-«k 0^75:0,
i/>^T'ab§o sisisst^. -^fflt-o^m. js^^, mmmiz^y)mf3:y)mzm^^
Ts.)V7)v^'-)^^'^'^^' jRfSMStt^ffi-rssi^. i^mmizj^^^f3i^^^> m
f3i5;4'©^5; Ar-B (OH) 2) ^, :^»©#&T. m\'c^m^m\^^fz.ti v^':^
^'(b-&i^®»SUVi'fiaj.hUTti. g^m^. >?-SzL — tHa=¥V-Hx [ (N.
N. N'. N'-5^h^^^;i'X5^^>~:^7s» ^ (n) ] ^u^-iYmt^^vf^
61
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4«fcTfT5t. s.mmf^om.m. jr^<^irj±^> ^iif:fei^**«#6.ns.
^<o-^m^^ti^Mz^^mMm\-imzwi^-^tifs.\r^f)^. m^i^it^mzj^y):^
\t. -^^iz. {i>m(D:&f^m\z^^x^BizjL7.v^Mt^m. ^hxt'^i^mz^m
)ummi^^. m7t^75,ji\:^mz^y)7s.ymmi^^^ ^vxmm^muM<Di^
62 '
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^-e^^T'bTiVi. ^mM\zm^<i:^m (i) *^7U— *tbT#e»ns«^. m
^fc, i^mmz^^^t^m (i) i::o»/^T#?>n2>a>«r©^'te#:
mm'&^^ lHI^m^^^^ tL^^^m-^?^.
^7.i7u-rhif'py>i-^ m ^m\*^^^t:\z^x>mmv. mm-r^^t.ii'^x
^j. fi^j, aais^, ^iS^J> ^mmm. i^uvy'n. vu-^n^ ^
xn. ^^n. ^"^n. mtfewm, .^^bs^j. s^^n^ ^-mn. u
63
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7}?U:t^'>x5^1/>3j5'J::r4^>'yDtri/>:/n«/^7ri#U-7--^©#®«tt^ ; t
ig-^^, ?»f^^J> ^B^J^ mf^m^mt3ii^^iiuxrcWi. ^m\z^K)wm^
64
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ffi-fb^j, mt. ^^^\z}it:sCxmmmmMs ^^im> mmm^ mmimu mm^tM^
mT5 h\ U :^=^^'>X5^l/>y ;Hf:$' 1/- : ^Jt-fbfflllci^fett^if
B7^{?iJi: LTtt. mmm- h U A, ^^M^DS^:^ b U '^7^, X— ; ^WM
\z)^n^Bmfs.mtvx\t. /^^:^=^>-^s#mx5^
m-r^mmmmzVT\t. mm^a. e^sr^s^ im&,m\zm'^mm^n^^mm
s^-r)\,zi-)um. m^mm. vu:3>?ft. ^mmiSEM^ ^j>mnm> Tjvu-jum.
^>-m\z!t^c. pHmmM> ^m^tn^ ^u-hm. mmmwmu m-^n. mnfs:^
^mmt^^^ffix^^o -^^iz. ^>>mizm\:^x^itmmiiFm^^-r^.^^^ Jkm.
^ii^j, mmn^ m0m. mmm^m. \fi^5.>m> ts/^. ^mm. Mmmm
Ajxti^mmnM\t. m%m m7.^t\ih. -^^t.. ^v h. ^^^^^
m) iz^n^^m-'^m. mz. \^hiz^n^mm'i'miz^
mx^^o :^%m\zt^i!)^^m.m<D^^m\t. m.^(Dmm> ^fife. itsu. i^m.
wo 02/22587
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M og, »^v<\ti oous^^^l^i 0 gv $e>ic:»*b<«i 0 O /igTiVi
b 5 g iil*S#Tf?J 30Aig:feViLl0g ^^n^n 1 iHl^fctm^slfc^V-tT
>m. ;\>^>h>mmm. wsmmi^mmmit^. ^m^i^m^^mm) . T^^^^.
/^U-mm^> mi^^^^Mm^^^Wmmm. Marchifava-Bignami^. ^'L-^
f^m^^^mim0k. i^3u-^u>m.mm. h-s^t.. ^^tt^j
wo 02/22587
PCT/JPOl/08058
mmm^t. sxT\z^tmmm(Dd!^f3i(o'ry^mmmm\zi)-^*-'^^wm^(Dmmizu^
)si^%^isa^x^mm^mizm\znm-r^ z. iitt^x-^. ■fy^i}^^^^h:i^mmmmiz
i!)-^i)^^wffm-^(Dmmiz^^n^o
1- (2-brUi?;i') -3 - (3-:?^ h=^->73:— -2-ZfU^>-l-^>
2-T-fe5^;VtfUS?> (25g) t3-;*b^e^'^>XTJl'5=^t:H (2 8g) <D
y^h^\^\'ny^>(l5 0ml)mm\Z^ ti^J^J^^ter t-Zfh^l^^}^ (2.
»H-NMR(400MHz, CDCag); 6 (ppm) 3.87(s, 3H), 6-96-6,99(m, IH), 7.24-
7.26(ni. IH), 7.32-7.34(m. 2H), 7.50(ddd. IH), 7.88(dt, IH), 7.91(d. IH). 8.19(td,
IH), 8.28(d, IH), 8.75(ddd, IH).
#^i?y2
2- (3-^>=^->7aix;P) -4- (2-fU>?;W - 4 V::^i5' >- b U
J.Chein.Soc..(1958)4193 izU^^. 1- (2-tfU5^JW "3- (3-^h
:^,>;7^-;v) - 2 -ya^>- 1 -:t> (17. 2 g) *^e>. ^i^tftt^^^^^-fb
^tl (1 6.7 g) ^mco
iH-NMR(400MHz, CDCI3); 6 (ppm) 3.80(dd, IH), 3.82(s, 3H), 4.00(dd, IH),
4.50(dd, IH), 6.86(dd, IH), 6.97(t, IH), 7.00-7.03(m, IH), 7.29(t, IH). 7.50(ddd,
IH), 7.86(td, IH), 8.07(td, IH), 8.65(ddd, IH).
##M3
2- (3-^b^v:7x-;i/) -4- (2-tfU>^;i') -4-:^^ViSS&
67
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J. HeterocycHc. Chem., 25, 799, (1988) iZ^l^^. 2 - ( 3 - 7^ b ^ ~> 37
-4- (2-tfUi^;W -4-i^^y:7*:$'>::.bU;i' (16.7g) ;J>^^x ^-fes
#:CD:^®'fb'&ife (12.3g) $#;fec
^H-NMR(400MH2, CDClg); d (ppm) 3.52-3.58(m, IH), 3.77(dd, IH), 3.79(s,
IH), 8.55(dd, IH), 6.82(ddd, IH), 6.85.6:89(m, IH), 6.94(t, IH), 6.98(d, IH),
7.47(ddd, IH), 7.83(dt, IH), 8.p2(d, IH), 8.67(ddd, IH).
##««J4
4- (2-^b^>':7x::^;w -2- (2-tfU5^;w -4-:r=^yiS^x5^;ux
2-br«;>^;i'g?^x5";i/x;?.7^;i/ (5.5 g) ®i?;^?;P7i^;i'AT5 (5
Oml) tr. *?&T6 0%7lc*<b:^hU'^7A (1.5g) ^tJHA^I^bfec 11^13
2-^ h^->:7i:?->';u:7*a-^'f r (7.7g) ^tP;^. *?^Tt? i ^f«^i«#
*^Mtt7KSfe. ^^^^ m^5/U:^7<Jr;i/*7A (i?Mx5^;P-^=^it>^)
TfJ^SL, g55^fi@<*:©^^<fc:^#f (6.6 g)
iH-NMR(400MHz, CPCI3); 6 (ppm) 1.20(t, 3H), 3.59(dd, IH), 3.88(s, 3H),
3.95(dd, IH), 4.11-4.20(m, 2H). 4.51(dd, IH), 6.94-7.00(m, 2H), 7.15-7.18(m, IH),
7.36(dt, IH), 7.43r7.47(m, IH), 7.65(td, IH), 7.73(dd, IH), 8.54-8.^6(m, IH).
4-7xXJl^- 2, 3. 4. 4 a-5=-h^t: Fn-5ff- (1) ^>\/H^y [4.
3-c] t:U:5^>?>-3-:^>
1 tCffi«©:&&lc:^UT-&fKU}t 4 - -AH- 2, 3 - t H O -
1 _y«Oyt:^>- 3 -g^i? (4.0 Og) SrX^y— ;V (6 Om 1) tC^^b, t
l» ^e?>— TKfqti ( 0 . 6 8 g) <^Sp;^ 3 ^WJP^a^tl^Tto C:^^
^^itsyu mmit^m (1.9 5 g, 49%) ^#fc.
iH-NMR(400MHzi DMSO-cl«); 5 (ppm) 3.65-3.84(m, 3H), 4.00(dd. IH), 6.91(dd,
IH), 7.04(ddd, IH). 7.27-7.41(m, 6H), 7.90(dd, IH), 11.18(s, IH).
##^J 6
68
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>?-fy^Pt!;i'T5> (6. 7inl) <Dy^h^}^\'uy^>mm (6 0ml) \Z
bUT'^^l'-r-r (1 5. 5 6g)O5=-b^fcHP7^>^?lK(3 0ml) 2^:
(12. 7 7 g)
iH-NMR(400MHz, CDCl^; d (ppm) 0.89(t, 9H), 1.10-1.15(m, 6H). 1.27-
1.36(m, 6H), 1.48-1.53(m, 6H), 4.06(s, 3H), 7.38<s, IH).
##^J7
3-^ DO- 6-^ h^->- 5-731— ;ni°u^-:^>
3-i7na-6-^b^i^-5-hU:/5^;W5">t!U^*5^> (3. 2 0g)
n^'^^^-fef^ (11. 5 7g) .5^h^^r;^ (hU73i::i;i'*:x:7xr » A^>^':7
A (4 2 8mg) , B^itm (I) (7 0mg) S:^r>>l^> (13 0ml) l^lUPx.,
h (i^^x5=-;w^^it>^) m^m^mcD^mik.'^m (i. log)
iH-NMR(400MHz. CDCI3); 6 (ppm) 4.16(s, 3H), 7.40(s, IH), 7.47-7.50(m, 3H),
7.60-7.63(m, 2H).
#3t^J8
6-i^Dn-4-:7:ii-;i/-3 (2H) -tfUi5^-:^y>
3_/7oa-6-p^b^~>-5-:73ix;H::'Ji5'>^>(2 6 7mg) tiS^BI(2
Mxg=-;i') T^^b^ m^mi^(ommit'^^ d 5 9mg) ^#:^o
»H-NMIl(400MHz, CDC1«); d (ppm) 7.38(s, IH), 7.47-7.49(m, 3H), 7.81-
7.84(m, 2H), 11.34(br8, IH).
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Q-^uu-2- (2-->Ty73in;w -4-:7x-;v-3 (2H) -trUrJ^'e^
6 -^UU-A-y3LZL)V- 3 (2H) -IfUyS^y > (8 Omg) . 2- (2
_5^7y:7i-;0 -1. 3. 2->^:^^^U-3t^U^-h (1 4 4nig) , i^e?^ (n)
(3 5mg) > hUX5^;i'T$> (107/il) . \f.^)V> (62/il) ©li^t:^5^U'>
(5ml) mmw^^ mmmmmrf. 4 Bmmwvrz. Kmu^m\iT >^nT7K
n-^b (i^mx5^;w^^rlJ->^) -rffiSb. 4S6H<^®^M'fb-&«^ (8 3mg)
»H-NMR(400MHz, CDCI3); 5 (ppm) 7.43(s, IH), 7.46-7.e0(in, 3H), 7:56(dt,
IH), 7.68(ddd, IH). 7.76(ddd, IH), 7.81-7.84(m, 3H).
10
TefraZiedran 50, 275-284, (1994) fctJ£oTPiSab:fc 2 - h U r^' x;i'
t;U5>^>(2. lOg), 3-i7nD-6-^h=^5^-5-7ai-;i/tfU:$^>^>
(8 0 Omg) . y'h^^T. ( h U 7a:x;i/3i^7.7 W » /'^^S^^^A (2 0 Smg)
:£4-~>l/> (1 0ml) icira^, ^m^H^T, 1 2 ot:-e2i^rpiM#u>^c:o Km
^■^mwommit-^^ (4 0 3mg)
^H-NMR(400MHz, GDag); 5 (ppm) 4.28(s, 3H), 7.37(t, IH), 7.46-7.53(m, 3H),
7.73-7.76(m, 2H). 8.52(s, IH), 8.94(d, 2H).
#^^«J 1 1
4-:7a:x;i/-6- (2-bfU^i^;w) -3 (2H) -tf'Ji$^e^y>
3_^l>c^.>_4-:7ai-;v-6- ( 2 - tf u a i^;^) t:U^*>^> (1. 0 7g)
<D 5 NSm^fi^ ( 1 5 m 1 ) ^ 2 BtF^^Jfl^jl^Ufc. 5 ti7^mit± h U ^ AmmX'
^fa^. mm^timmv. it®!x5^;vT^#uT> m^mi^ommit^m (6 o 9
mg)
70
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^H-NMR(400MHz, CDCI3); 5 (ppm) 7.38(t, IH), 7.47.7.53(in, 3H), 7.95-
7.98(in. 2H), 8.60(s, IH), 8.95(d, 2H).
12
T-b:^;HfU-:?> (2.4 6 g) ^B^m (4inl) t^^U 7 0'CJCJn^U^7&«
e,, (1.1ml) ^^M^-^rtCjgTbfc. SfS*£'^^ia^Ti5c?&^. *tmbfcMS
Srit^bfco ffi^^B (4.8 g) lCMmzK«:^hU':7i:.7K^^2rJn;^. S^mx5^;i.T?
tgSSbfc. (4.0 6 g) 5?pt5^;i'3j^;V'AT^F (5 0ml) izmMV. Ti^
Yb^hUC^A (1.5 g) &iPx.. Mm\zx 2 mmmWV fto zK^Jd;^. S^^x?^;!/
MEET?^^U. ^i^Jftit^O^fi^b'^tJ^^fco (2.7 4 g, 8 3 %)
^H-NMR (400MHz. CDCI3); S (ppm) 4.87 (s, 2H), 7.51-7.55 (m, IH). 7.87-7.91
(m, IH), 8.09 (d. J=8.0 Hz, IH), 8.66 (dt, J=4.8 Hz, 0.8 Hz, IH).
0mm 1 3
2-t!us;;i/-T$yp^5^;i'-2 ' --^u^y K^V>
2- (7$^KT-t^;W tf'J-:^> (2.7 g) <&x^y— (56ml)
2-yo^:7aL-;i/bF^5^> (3.4 g) *Sn^, ^iaicT-il*it#Ufeo MET
Igi^U. 3Set^7^b^t: Fo:7^> (40ml) tr^«?U> h «J :7aix;i/3l>X:7.Y
> (4.94g) ^iMXMUiZXSmmmWVr^o Tic (iml) $:tDAll^P«^«#U
ti^jvij^J^i^^-^hi^yy^- (^=^iJ->-S^Kx^;w^) T^SIb, ^ifelAtfe
®«M{k^tl (2-6 9g. 5 3%)
^H-NMR (400MHz, CDCI3); a (ppm) 1-84 (brs, 2H), 4.41 (s, 2H), 6.74 (td,
J=8.4 Hz, 1.2 Hz, IH), 7.16-7.17 (m, IH), 7.25-7.30 (m, IH), 7.45 (dd, J=8.0 Hz,
1.2 Hz, IH), 7.62 (dd. J=8.4 Hz, 1.6 Hz, IH), 7.67 (td. J=8.0 Hz. 0.8 Hz, IH), 8.14
(d, J=8.0Hz, IH), 8.50-8.51 (m, IH). 11.39 (brs, IH).
##^»J14
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2- (2-:/D^:7i-;i') -6- ( 2 - tf u i?;^) -4, 5-i?kFn-i. 2.
2_tfiji;;i,-T5/;^5^;i,_2 '-:rD^7xn;V't H^l/> (2.6 9 g) S
il7fC7^h^kf^P7^> (10 0ml) fc^j^bfco ^acJ^Tx hU3}^;^y> (i.
3 1 g) thUx^;i/75> (2.7ml) <£lni^. 0'Cd^^)^*{c:mtaS"T?^taL'
(Drnmit-^^ (i-o 0 3i%)*#fc.
^H-NMR (400MHz, CDClg); 6 (ppm) 4.79 (s, 2H), 5.50 (s, IH), 7.23-7.30 (m,
2H), 7.39-7.48 (m, IH), 7.53 (dd, J=7.8 Hz, 1.8 Hz, IH), 7.67-7.72 (m, 2H), 8.04 (d,
J=8.0 Hz, IH), 8.57 (ddd, J=4.8 Hz, 1.8 Hz, 1.0 Hz, IH).
ESI-Mass; 331 [M*+H]
mmm i
2- (2-:/ot:73i::i;i') -4- (3-^ l-^->7a:— ;i/) -6- (2-t:'J>^
;p) -4, 5->^t:FD-3 (2M> -\fV^z^y>
Indian J. Chem., Sect. B30 (1991) 6, 589lc:fi!ti. 2 - ( 3 - xn;P)
-4- (2-tr>jV;W -4-:^=^^ViSm (3g) t 2-:/0^::7ain;i't K^>?
> (2g) d^e>. ^i^@#:c^^M<b-&#i (1.1 g) ^^fi'to
^H-NMR(400MHz, CDCI3); 6 (ppm) 3.44-3.86(m, 2H), 3.73(s, 3H), 3.94-4.15(m,
IH), 6.81(dd. IH), 6.97-7.01(m, 2H), 7.21-7.29(m, 3H), 7.37.7.41(m, 2H). 7.65-
7.69(m, 2H), 8.05(d, IH), 8.61-8.63(m, IH).
2- (2-:/n^7xZi;P) -4- (3 - 1 Hd^^S^^xz:;!/) -6- (2-HU
5;;!,) -4, 5->^tHa-3 (2H) -fUi5^e^/>
2- (2-7*D^-7xn;V) -4- i3 - ?^h^i^y aL=.)V) -6 - (2-k-U
>?;W) -4, 5-v^tiHP-3 (2H) -t!U:S^v^y> (l-.lg) <^i?^POP^
^>m^i2 0ml) tc. i>K?&T, lM3i?n>hU:/o-R'-r mifc:>^5^U>^?^ (7
ml) lBtr^im*^bfc. iK^JO^, T>^nT7K-a^mx5^;i/lr:^SBU
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%m (0.8 g) ^m^o
»H-lSIMR(400MHz. CDClg) ; (5 (ppm) 4.00(brs, 2H), 4.12(brs, IH), 6.68(dd,
IH), 6.84-6.89(in. 2H). 7.13(t, IH), 7.23-7.31(m, 2H), 7.36-7.46(m, 2H), 7.65-
7.71(m, 2H), 8.04(d, IH), 8.60-8.62(111, IH),
2- (2-7*p^:73i-;p) -4- [3- (2-t:b'D^^->xhJ^>') r?!";!/]
-6- (2-t!U>^;l') -3 (2H) -tfU:^^?y>
2- (2-yD^:7ac-;W -4- ( 3 - 1 H □^>':7a:-;W -6- (2-l:f
5-e?fcHn-3 (2J^ -tfU^i?/> (1 7 Smg) <DS?^5^
;1/3}n;1/ATS (5m l) \Z.%'^~V. 6 0 %7K^ik:M- U A (4 Omg) ^
t^TL. 3 0:^it#m. (2-:7n«h4rv') - t e r t -:/5^;i/>»^5";i/~>^ >
(3 0 Omg) ^iJQ^, ■MMr^-mMW\^t^o eif^x5^;V^SP;^, 7K^5fe,
iy^yp^)\^tizfK (@^mx5^;i/---x^i}->^) -cm^bfco ^#e»tife^^?ft
t^Wi5^h7t:]<n:7^> (5ml) Id^/iPU, 5Nmm (Im 1 ) 0^
=E}Uy 7 7.<Dmm<t'^^ (1 1 img)
iH-NMR(400MHz, CDCI3); 6 (ppm) 3.94-3.99(m, 2H), 4.l6(t, 2H), 7.02<dd,
IH). 7.32-7.41(m. 3H), 7.49-7.58(in, 3H), 7.68-7.79(m, 3H), 8.14(dt, IH). 8.67-
8.68(in,2H). .
2- i2-zyTyyx.=i}V) -4- [3- (2-t:Ha^->X^=^~» 7xx;^]
-6- (2-tfU>^;W -3 (2/i) -tfU^5^y>
2- (2-7*D^:7xx;i') -4 - [3- (2-k Fn^v'Xh^v') 7xx;i/]
-6- (2-tf U>^;W - 3 (2iJ) -HUiS^i^y> (7 Omg) ©i^^^^;^!}^;!^
(3ml) fc, vTMfc^ (I) (2 Omg) ^iJD;^, 120'Ct?l
73
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(5 Omg) ^#;feo
^H-NME(400MHz, CDCI3); 5 (ppm) 3.96-4.00(m, 2H), 4.16(t, 2H), 7.04(ddd,
IH), 7.35(ddd. IH), 7.40(t. IH), 7.52-7.61(m, 3H), 7.74-7.89(in, 4H). 8.22(dt, IH).
8.64(s, IH), 8.67-8,69(m, IH).
2- (2-:/n^7x:=:;W -6 - ( 2 -p^ h^->7acli;W -4- (2-tfUi?
4- (2-j?^h^'>7xn;w -2 - (2tf'Je?;i') -4-:r=^yiS^x5^;i^x
Xt^jI' (1. i4g) ©x:$7y-;^^^lK (i6mi) 2-:;^n^7xx;kti H
^v?> (6 8 img) ^im^. 8 OXlfSl^ra^Ufc. J5JS?1'&#I$:SI^^. —
hD^>-li> (2 0ml ) 1 8 O'C-e— Bfe^^^Ufc. SJSS'&^Srg^ffiJX
X5^jl,-^^-t>->?S) -e^MU, (2 9 4mg) ^#fcc
^H-NMR(4001\4Hz, CJDCls); 5 (ppm) 3.91(s, 3H), 6.99-7.05(ni, 2H), 7.31-
7.42(ni. 3H), 7.48(td, IH), 7.55(dd, IH), 7.62(dd. IH). 7.76-7.80(m, 2H). 8.70-
8.72(m, IH), 8.74(dt, IH), 8.78(s, IH).
M«?y 6
2- (2-->T7:7iX;i') -4->'ix;V'- 2, 3, 4, 4a-5^h^fcKa-
5_fj_ (1) ^>yt:^/ [4. 3-c] HU37'>^>-3-:t>
4_7xx;i.-2. 3. 4, 4a-7^h^t:KO-5if- (1) ^>yif^y [4.
3- c] bfU:$^>?>-3-:^-> (9 7 4mg) ^:^<b^5^l^> (2 0ml)
U 2- (2-'>Ty7aix;V) -1. 3. 2 - >?:^=^-9-^ 'J h (1.9 6g) ,
m^m ( 1 . 2 7 g) *5 h u x^;vT5 > ( 1 ^ 0 6 g) ^■mxm.u^zx—mM
#Ufec SJ;S?i^^i^mx5^;H?#SRb, T>^-T7j<v 1 N^^43 J:D^^fn:^^7jc
(^^it^-S^mx^^jl/^) Tfffigibfco #6nfca^S^SlF^x^;i'
-^=t^-y->*^e:S^abT^^^fc^^ (14 Omg. 11%)
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iH-NMR(400MHz, CDCI3); <5 (ppm) 3.66-3.79(m, 2H), 3.93-4.01(m, IH), 4.04-
4.13(m, IH), 6.89-6.94(m, IH), 6.99-7.05(m. IH), 7.29-7.40(m, 4H), 7.41-7.48(m,
3H). 7.61-7.72(m, 2H), 7.72-7.77(m, IH), 8.03(dd, IH).
2- (2— >7y7x-;V) -4-7ai:;:i;P-2, 3.->?t Hn- 5 if- (1)
>Vt?^y [4. 3-c] t:U:$^'i?>-3-:t>
2_ (2-->Ty^3i:^;i/) -4-:7ai— ;W-2, 3. 4. 4a— T^b^tl^o
-SH- (1) ^>\/kr^y [4. 3-c] tfU^>^>-3-*> Olmg) ^
eO'Cg^^ (4ml) IC^^SU (4 2mg) ^Jp;l 7 oriclT 3 0:«-m^
e^U;^3yj^;ib^A (^4^i^->-g^i^x5^;^^) (l4m-g^ i
5%) ^#;^Co
»H-NMR(400MHz, CDCJla); 6 (ppm) 5.06(s, 2H). 6.98-7.02(m, IH). 7.07-7. 13(m,
IH). 7.33-7.38(m, IH), 7.38-7.43(m, 2H), 7.46-7.58(m. 4H), 7.71-7.80(m, 2H),
7.82-7.87(m, IH). 8.03-8.08(ni, IH).
2- (2-3-H:7 3i^;i/) -4- (3-tfU5?;W -2. 3. 4, 4a-5=-h^
tHa-5H- (1) ^>^/H^y [4. 3-c3 HUi5'*S?>-3-:a->
iH-NMR(400MHz, CDCls); 5 (ppm) 3.65-3.83(m, 2H), 3.95-4.10(m, 2H), 6.93(d,
IH), 6.97-7.05(m, IH). 7.10-7.17(m, IH), 7.29-7.37(m, IH). 7.37-7.44(m, IH),
7.44.7.56(m, 2H). 7.64-7.77(m. IH), 7.90-8.03(m, 2H), 8.54(d, IH), 8.«4(dd, IH).
2- .(2-v'Ty:7acx;i') -4- (3-ifU~:^;w -2. 3 -v^th'o-s h-
(1) ><>ytf^y [4. 3-c] If ij^*e^>-3-:^->
2- (2-3-F:7xx;W -4- (3-tfU>>;W -2. 3. 4. 4a-xh
^tKO-5if- (1) ^Wtf^/ [4, 3-c] tfU3^i?>-3-:r> (75
75
wo 02/22587
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jj^g) -p^5^ji.-2-t°DU H> (2inl) \zmMVs l^TXtM^ (5 5m
g) ^^Z^y'h'p^T. (hU:7x— ;i/^7.:7^' » A^z^^A (5mg) ^iU^.
5 7%) &#:'t<.
»H-NMR(400MHz. DMSO-de); d (ppm) 5.21(s. 2H), 7.10(d, IH), 7.12-7.20(m,
IH). 7.42-7.48(m, IH). 7.56-7.61(in, IH), 7.70-7.77(in, IH), 7.88-8.00(m, 4H),
8.07-8.12(m, IH), 8.64-8.75(ni, 2H).
UliSI^ 10
Z -^^-M )V^n\^^>m. (CAS No. 20 51 -95-8) t2-h;W
;HiH^v^>^^^ (CAS No. 6 3 5-2 6-7) d^e>-&^$n^ 6 -:7xn
)V-2- (2-h;K;W -2. 3. 4, 5-T-h^tHPb:U^*e^>-3 (2/J)
(0.5 4 g) S:x^^tHD:7^> (2 0ml) tC^^SU - 7 8 "C Idi^j^l
1.5MU^'^A-:^'1'yyDt!;WTS H (1.2ml) t:^^\ZlSi^rz^. 4-
T::^;^7;i^5't F (0.2 7 g> ©5" b ^ b Hd7^>^?S (1 Om.l) ^^^izlm
xi^mv. mmit^m o . i o g
iH-NMR(400MHz, CDCl^); 6 (ppm) 2.19(s. 3H). 3.83(s. 3H), 3.95(s, 2H), 6.88-
6.94(m, 2H), 7.24-7.28(iq. 2H). 7.29-7.36(m, 4H), 7.37-7.40(ni, 2H). 7.45-7.48(m,
IH), 7.66-7.70(m, 2H), 7.82-7.85(m, IH).
^is^j 1 1
2, 6-S?7xx;i.-4- (a-l::h*P^~>-2-en«j;P) -4, 5-S^fcHD
-3 (2iJ) -b!'JiS^5^^>
3_^s;>./>f;i,^Ptf^>^ (CAS No.2 0 5 1-9 5-8) ^7x::^;H:i
wo 02/22587
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\i^i>>M^^ (CAS No. 10 0-63-0) -^^^-^fSi^tl^ 2 , 6 -i^y:r.
-;W-2. 3. 4, 5-5^h^kHnk°Ui5''>'>-3 (2H) (0.1 Og)
fc2-t:Ue?>:'!3>>W3i^^>'T;i/xt:H (0.0 5 g) $r5^h^fc Hn:?^^ (lOm
1) IC^^U -7 8'CJr?&^^. 1.5MU5^':7A5?-ry::^nt!Jl/T5H (0.2
ml) ^^f-^flcJn^fc. lf^r^lKJS^m^. 2-t;U>^>*;i/jJ?#~>TJl^5^kF (0.
0 5g) i:1.5MU^'^A>'-f y7'nfcf;l/T5 H (0.2ml) S:$e>CSn;t. 2
^) iCT^iSU. ^0'fb'&«b2 3mg2:#fco
iH-NMR(400MHz, CDCL^; d (ppm) 2.75(dd, IH), 3.13(dd, IH), 3.23(ddd, IH),
4.25(brs. IH). 5.68(brs. IH), 7.24-7.31(m, 2H), 7.33-7.39(m, 3H). 7.40-7.46(ni,
2H), 7.51(dd, IH), 7.59-7.63(m, 2H). 7.66-7.71(m, 2H), 7.76(dt, IH), 8.55-8.58(m,
IH).
^J£^12
2_ (2-i^7/:7x-;i') -4- (4-*;U3i>uyx5^;i/T5y:^;W3j^— ^i') -
6-:7xx;w-3 (2ji) -t!U^-:^y>
4_;7 3^-;^-4-:r=^v-i&Mx5^;^x:^5^;^«:PSau^ t h^>^>— TKio^^t
^;S;$-&T6-:7^x;i.-4-xh:^->:i7;i'3i^x;p-4. s-v'th'a-s (2H)
- 1! 'J ^*v^y >^-&fi£Ufcm, g^m't'rft^^f^ffl 6 - :7xx;i/- 4 -X
->^;i^3Hx;k-3 (2Ji) -t!U^>^y>tl-:fc. 6-7aix;i'-4-xb^~>:^j
jV7}?-;U-3 (2H) -t!'J:$^5^y> (2.0 0 g) $:v^i7PDpt^> (SOml)
ic^^b, 4- (2-T5yx^;i/) ^:;W3i^u> (i.eog) 2g^ijp^
y — </^:^m:^<t LT 4 - ( 4 -^jw^Jk 'J y x^;i/T 5 y :t>;W3Hx
-6-7xX;i/-3 (2iJ) -t°Ui5^>^y> (1.8 3 g) ^^fco 4- (4-
:E;i/7Kuyx5^;wy^y*;w3!?x;w -6-yaix;^-3 (2h) -hru^*2^y>
(0.3 6 g) i:2-:::^a^:^>Vxhij;i/ (0.5 Og) 2->^i^o
wo 02/22587
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n^>if> (15ml) {C^^$-ii:> m (0.2 g) i@^m:^7U'^A (1.0 g) ^
nx. 1 9 orfcTn^FBrn^bfco Kmm\zmk:^^)v^isax. a^mx^^ mm^
mmt^m i 3 m g
^H-NMR(400MHz, CDCI3); 6 (ppm) 2.48-2.66(m, 6H), 3.58-3.76(m, 6H), 7.45-
7.51(in, 3H), 7.62(dt, IH), 7.70(dd, IH), 7.80(dt, IH), 7.86-7.94(m. 3H), 8.84(s.
IH), 9.58(brs, IH).
lUSI^ 13
2- (2-->T/7x-;U) -6- (2-t;Ui?;W -4. 5-i^tKn-2/f-
tfU:5^i^>' C4, 5-b] ^>V''7 7>-3-:t>
2- (2-3^D^:7x-;i') -4- (2-t HD:^^S^37air:;P) -6 - (2- t;
Ui?;!/) -4. S-v'tHn-S (2JtO -tfU3^>'/> (2 0 Omg) <?)i^pt5^
;P7f:;i/A7S H^^g (6ml) \Z'^7>itm (I) (8 5mg) JPX-^ 1 2 Ot:"^
(OWMit'^m (3 img) ^#fco
iH-NMR(400MHz, Ca)C3l8); 6 (ppm) 7.46(ddd. IH), 7.54(td, IH), 7.60(td, IH),
7.65(ddd, IH), 7.77-7.85(111, 3H), 7.88-7.93(m, 2H), 8.26(td, IH), 8-33-8.35(m,
IH), 8.88-8.90(m, IH).
mMm 14
2- (2-::^D^:7xrL;w -4- (2-;?^ h^e^:7aix;i.) -6- (2— truv^
;W -4, 5--:^kFP-3 (2/i) -tfU:?'2^>'>
^H-NMR(400MH2, CDCI3); (5 (ppm) 3.47(brs, IH), 3.80(brs, IH), 3.84(s, 3H),
4.29(brs, IH). 6.90-6.95(m, 2H), 6.96-7.29(m, 3H), 7.43(td, IH), 7.51-7.54(m, IH),
7.65-7.71(m, 2H), 8.07(dt, IH), 8.58(d, IH).
HJfi^l 5
2- (2-yoqE7x:i^;i') -4- (4-;* h=^5^:7xx;w) -6- (2-t!U>?
78
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iH-NMR(400MHz, CDCI3); 6 (ppm) 3.78(s, 3H), 3.79(brs, 2H), 4.04(brs, IH),
6.86(d. 2H), 7.24:7.34(m, 4H), 7.37.7.44(m, 2H). 7.67-7.71(m, 2H). 8.04-8.08(m,
IH), 8.62-8.64(in, IH).
2- (2-::^ni^r:7n:n;w -4- (3-:;^d^-6-p^ h=^^">:7ain;v) -6-
iH-NMR(400MHz, CDCla); 6 (ppm) 3.36-3.46(m, IH), 3.82(s, 3H), 3.82-
3.90(m, IH). 4.14-4.26(m, IH). 6.78(d, IH). 7.25-7.29(m, 2H), 7.35-7.72(m, 4H).
7.66-7.71(m, 2H), 8.07(d, 2H), 8.58(d, IH).
2- (2-3-K7:c-;W -4- (2 h=^->:7a:ri;W -6- (2-tr'Ji?
;P) -4. 5-i?tKO-3 (2Jy) -lfU:$''v?y>
»H.NMR(400MHz, CDCl^; 6 (ppm) 3.85(s, 3H), 3.86(brs, IH), 4.30(brs, IH),
6.90-6.97(m, 2H), 7.08-7.13(m, IH), 7.24-7.79(m, 3H), 7.44-7.51(m. 2H), 7.66-
7.71(m, IH). 7.95(dd, IH), 8.09(d. IH). 8.56-8.59(m, IH).
18-
4- (2-p^h^s^:7xzi;i') -2-:7x-;i/-6- (2-trUi?;W -4. 5-
^H-NMR(400MHz, GDCls); 6 (ppm) 3.47(dd, IH), 3.75(dd, IH), 3.85(s, 3H),
4.28(dd, lH), .6.91-6.95(m. 2H). 7.21(dd. IH). 7.24-7.30(m, 3H). 7.41-7.45(m, 2H),
7.65-7.73(m. 3H), 8.15(dt, IH), 8.56-8.58(m. IH).
2- (2->'*a^:7x^;i/) -4-:7x-;i/-6- (2-t!'J>';i') -4, 5->?
tHO-3 (2H) -fUiS'*i^y>
iH-NMR(400MHz, CDClg); 5 (ppm) 3:50-3.70(m. IH), 4.00-4.20(m, 2H),
7.24-7.35(m. 5H), 7.39-7.44(m. 4H), 7.66-7.72(m, 2H). 8.06(d, IH), 8.62.8.64(m,
IH).
79
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2- (2->^n^;>'x-;i/) -4-7x-;V-6- (3-tfUi^>'l') -4, 5->?
^H-NMR(400MH2, CDCla); 5 (ppm) 3.40-3.49(in, 2H). 4.01-4. 14(m, lH)i
7.23-7.47(m, 9H), 7.67(d, IH), 8.07(d, IH), 8.62(dd, IH), 8.95(s, IH).
siis^sj 2 1
4, 6-$>7ai::i;l'-2- (2-tfU5^;W -4, 5-5^tHn-3 (2iJ) -tf
iH-NMR(400]V[H2, CDCI3); 5 (ppm) 3.42(dd, 2H), 4.05(dd, IH), 7.22-7.40(m,
9H), 7.56(dt, IH), 7.76-7.80(iii, IH), 8.59-8.61(m, IH).
mmm 22
4_ (2-;*h:^->:7x-;v) -2- (2-b*'j>';w) -6- (2-tfue^;W -
4. 5-S?t:Ho-3 (2iJ) -tfU3;^-:^y>
^H-NMR(400MHz, CDCI3): d (ppm) 3.51(dd, IH), 3.79(dd, IH), 3.81(s, 3H),
4.32(dd, IH), 6.88-6.95(m, 2H), 7.21-7.28(m, 4H), 7.60-7.69(m, 2H), 7.75-7.79(m,
IH), 8.15(dt, IH), 8.54-8-55(m, IH), 8.61-8.62(m, IH).
HSg^J 2 3
4_ (2-->Ty:7a:-;i/) -2-:7xn;i/-6- (2-ifu>^;0 -s (2h)
»H-NMR(400MHz, CDCI9); 6 (ppm) 7.35(ddd, IH), 7.42-7.46(m, IH), 7.51-
7.57(m, 3H), 7.70(td, IH). 7.75-7.83(m. 5H), 8.21(dt, IH), 8.65(s, IH), 8.65-
8.67(m, IH).
USS^J 2 4
2- (2-yD^:7ai^;P) -4- ( 2 - h^->:7 x-;P) - 6- (3-fc:U>^
;i/) -4. 5->'kHn-3 (2JJ) -lfU:$^>^y>
»H-NMR(400MH2, CDQa); 6 (ppm) 3.35<dd, IH), 3.46(dd, IH), 3.87(s, 3H),
4.33(brs, IH), 6.93-6.99(m, 2H), 7.23-7.32(m, 4H), 7.44(td, IH), 7.70(dd, IH),
8.05-8. 10(m, IH). 8.60(dd, IH), 8.89-8.93(m, IH).
80
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mmm2 5
4- (2-:/p^:7x:^;i') -2-:7x-;i/-6- ca-tfUv';!-) -4. s-v?
iH.l'3MR(400MHz. CDCI3); 5 (ppm) 3.41(dd, IH). 3.87(dd, IH), 4.49(dd, IH),
7.13-7.17(m, IH), 7.25r7.34(m, 4H), 7.42-7 AUm, 2H), 7.60-7.74(m, 4H). 8.15(dt,
IH), 8.57-8.59(m„lH).
II»J 2 6
.2- (2-p^b^>7x^;i') -4-:7x-;i'-6- (2-t!U>';i/) -4. 5-
iH-NMR(400MHz. CDCI9); 5 (ppm) 3.58(dd, IH), 3.77(s. 3H). 3.78-3.«7(m,
IH). 4.08(t. IH), 7:00(d, IH). 7.03(td. IH), 7.23-7.43(111, 8H), 7.64(ddd, IH),
8.03(dt, IH), 8.58-8.60(m, IH).
^»J2 7
4_73,-;V,-2- (2-3=.ha7x::i;W) -6- (2-tfU~:^Jl') -4,
»H-NMR(400MHz, CDCI3); 5 (ppm) 3.70(dd, IH), 3.78(dd, IH), 4.06(dd. IH).
7.26-7.39(m. 6H), 7.46-7.52(m, IH). 7.67-7.74(m, 3H). 7.97.8.02(m, 2H). 8.61-
8.64(m, IH).
llSfi^J 2 8
2- (2-7;W:ta:7:i:n;i/) -4-:7x-;l'-6- (2-fc!U>^;W -4, 5-
iH-NMR(400MHz, CDCI3): <5 (ppm) 3.64(dd, IH), 3.83(dd, IH), 4.10(dd, IH),
7.15-7.40(m, 9H). 7.46(dd. IH). 7.70(ddd, IH), 8.07(dt, IH), 8.61-8.63(m. IH).
2 9
2- (2->^P^:7x-;W -4- (2-kFD^~>:7x::^;W -6- (2-t!U
_4, 5-S?hHa-3 (2H) -tf'JiS^i?/>
^H-NMR(400MHz, CDCi^; 6 (ppm) 3.47(brs, IH), 4.25(brs, IH), 4.43(brs,
81
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IH), 6.81(t(i, IH). 6.97(d, IH), 7.10(d, IH), 7.18(td, IH), 7.25-7.44(in, 4H),
7.68(brs, IH), 7.74(td, IH), 8.10(dt, IH), 8-72(d, IH).
2- (2-yn^7ac-;W -4- (4-t:Ha^>'7a:-;i/) -6- (2-eU
5^;i/) -4, 5-i<bb*D-3 (2Ji) -l:fU:5^>'/>
»H-NMR(400MHz, CDClg); 6 (ppm) 3.60(brs, 2H), 4.02(brs, IH), 5.20(s, IH),
6.74(d, 2H), 7.23-7.32(m, 4H), 7.38-7.44(m, 2H), 7.67-7.72(m. 2H), 8.06(d, IH),
8-62-8.64(m, IH).
mmms i
2- (2-yPt7air:;i/') -6- (2 - 1 Kn^rS^^i— -4- (2-t!U
v*;!/) - 3 ( 2 ij) - tr u^i^y >
iH-NMR(400MHz, CDCI3); 5 (ppm) 7.01-7.05(m, 2H), 7.34.7.43(m, 3H),
7.50-7.56(m, 2H), 7.89(d. IH). 8.76-8.79(in, 2H), 9.08(s. IH), 10.60(s, IH).
4- (2-tHn:^>>7ai:^;W) -2-:7x-;v-6- (2-fc!U>^;W -3 (2
iH-NMR(400MHz, CDCI3); 6 (ppm) 7.05-7.1O(m, 2H), 7.36-7.45(m. 2H),
7.56(dd, IH), 7,64(ddd, IH). 7-77.7.84(m, 3H), 7.90(dd, IH), 8.23(d, IH), 8.88-
8.92(m, IH), 8.78(s, IH), 9.05(brs, IH).
3 3
4- (2-bHa=^->73iii;i» -2-7jc-;1/-6- (2-tfU>^;V) -4. 5
->?tKo-3 (2fJ) -tfU^>^/>
iH-NME(400MHz, CDCI3); 5 (ppm) 3.43(dd, IH), 4.30(dd, IH), 6.84(td, IH),
7.01-7.09(m, 2H), 7.32-7.37(m, IH), 7.41-7.48(m, 3H), 7.55-7.58(iii, 2H). 7.82(td,
IH), 8.20-8.22(m, IH), 8.58(s, IH), 8.76-8.77(m, IH).
IIWJ3 4
2- (2-:/a^73i-;i/) -4- (2-t HP^i^7xn;i/) —6- (3-fc:'J
S?;i/) -4. 5— :?t:Ha-3 (2iJ) -tfUiS^5^y>
82
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iH-NMR(400MHz, CDCI3); 6 (ppm) 3.43(dd, IH), 3.54-3.63<m, IS). 4.35-
4.44(m, IH), 6.82-6.88(in, 2H), 7.05(brs, IH), 7.14(td, IH), 7.26(td, IH). 7.36-
7.45(m, 3H). 7.66(d, IH), 8.18(dt, IH), 8.66(dd, IH), 9.00(s. IH).
MI3IIJi«9J3e«®:^1*J^*l^T:^*S^3 5 75M3 8®^M<fc^i^*^fiKl-:fe.
HJfiini 3 5
2- (2->^n^:73i:i;i/) -4- (2 yxh^^^^^i-;!/) -6
- (2-tfUv^;W -3 (2 if) -tfUiS^~:^/>
iH-NMR(400MHz, CJDCla); 6 (ppm) 2.25(s. 6H). 2.72(t, 2H), 4.10-4.16(m. 2H),
7.00(d, IH), 7.03(td, IH). 7.29-7.39(m, 3H), 7.48(td. IH), 7.54(dd, IH), 7.60(dd,
IH), 7.72-7.77(m. 2H), 8.13(dt, IH), 8.62(s. IH). 8.63-8.65(m, IH).
|lli£l»J3 6
2- (2-:/n^>'ain;w -6- (2 -5?p^^;i'T5 y xh^rv':73:-;w) -4
- (2-b°Uv'Jl') -3 i2M) -t!Ui5^>'/>
*H-NMR(400MHz, CDCI3); a (ppm) 2.24(s, 6H), 2.77-2.83(m, 2H). 4.20<t, 2H),
6.99-7.05(m. 2H). 7.30-7.41(m, 3H), 7.48(td, IH), 7.S6(dd, IH), 7.66(dd, IH),
8.69-8.71(m, IH), 8.74-8.77(m, IH), 8.95(s, IH).
llli«»J3 7
2_ (2-:/D^^ai^;l') -4- [3- ( 2 - tzi U ;l':t^->:7a::^;W) ] -6
- (2-fUv';i') -3 (2H) -t!UiS'*i?/>
iH-NMR(400MHz, CDCI3); 6 (ppm) 5.2(s, 2H), 7.07(dd, IH), 7.21-7.24<m, IH),
7.32-7.40(m. 3H), 7.49-7.63(m, 4H). 7.70-7.79(m, 4H), 8.14(d, IH), 8.59-8-61(m,
IH), 8.65(s, IH), 8.67-8.69(m, IH).
2_:7x-;p-6- (2-t?Uv';w -4- (2-hU:7;i^:i-Dp^5^;i/x;w:a^^;i^
:j-^e^7x^;i-) -4, 5->?tFO-3 (2H) -lfUi$^S?y>
^H-NMR(400MHz, CDCls); 6 (ppm) 3.34(dd, IH), 4.01(dd, IH), 4.31(dd, IH),
7.28-7.33(m, 2H), 7.36-7.48(m, 6H), 7.63(dd, 2H), 7.74(dt, IH), 8.17(td, IH),
8.60(ddd, IH).
83
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2- (2-v'7/7i-;i') -4- h^>^:7xn;i/) -6- (2-t!Ui^
J0 -4. 5->^kHo-3 (2ii) -fc!Ui5^5^>/>
iH-NMR(400MH2, CDCI3); 6 (ppm) 3.50(dd, IH), 3.86(s, 3H), 3.88(dd, IH),
4.29(dd. IH), 6.92-6.98(m, 2H), 7.2B-7.31(m, 3H), 7.43(ddd. IH), 7.65-7.78(m,
4H). 8.17(dt, IH), 8.57-8.59(m, IH).
2- (2-'>Ty73i::i;i') -4- (2 -p^ h^>^7xri;W -6- (2-trUi?
JW) -3 (2fO -liU:$^>^y>
iH-NMR(400MHz, CDCI3); <5 (ppm) 3.87(s, IH), 7.01(d, IH), 7.04(td, IH).
7.33(ddd, IH), 7.41(ddd, IH), 7.50-7.56(m, 2H), 7.73<td, IH), 7.76-7.81(m,
2H). 7.85(dd, IH), 8.23(td. IH). 8.54(s, IH), 8.62-8.66(m, IH).
|IJ£«»J4 1
2- (2->'T/73i— ;i/) -4- (2-k KO^^^S^^i— ;W -6- (2-eU
z^)V) -4. S-v'tHP-S (2ii) -IfU^J'v^y^
iH-NMR(400MHz, CJDClg); 6 (ppm) 3.56(dd, IH), 4.14(dd. IH), 4.42(dd. IH),
6.85(td, IH), 6.96(dd, IH), 7.14(dd, IH). 7.20rtd, IH). 7.38(ddd, IH), 7.46(td,
IH), 7.58(dd, IH). 7.70(td, IH). 7.74-7.78(m, 2H), 8.17.(dt. IH), 8.70(dt, IH).
^JS^J4 2
2- (2-'>7yr'a::::;W -4- ( 2 - 1 h* O^v^^xZi;^ -6- (2-tf'J
>?;p) -3 (2ji) -t!u^-:^y>
^H-NMR(400MHz, CDCI3); 6 (ppm) 7.05-7.11(m, 2H), 7.38(ddd, IH), 7.43(ddd.
IH), 7.56(dd, IH), 7.64(ddd, IH), 7.78-7.84(m, 3H), 7.89-7.92(m, IH), 8.23(td,
IH), 8.24-8.71(m, IH), 8.78(s, IH), 9.04(s. IH).
lt»J4 3
2- (2-->7y:7a:-;i^) - 4 6 - (2-t!U5^;i') -3 (2fi)
84
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iH-lSIMR(400MHz, CDCI3); 6 (ppm) 7.35(ddd, IH), 7.46-7."50(m, SH),
7.57(ddd, IH), 7.74-7.82(m. 3H). 7.88(dd, IH), 7.95-7.97<m. 2H). 8.23(td, IH).
8.63(s, IH), 8.67-8.69(m, IH).
2- (2-5^Ty:73^-;i') -4- (3-::^p^-6-^h^i^7air:;w -6-
(2-tiU>^;V') -3 (2ff) -tfU:5^i^>'>
iHNMR(400MHz, CDCI3); (5 (ppm) 3.85(s, 3H), 6.88(d, IH). 7.34(ddd, IH).
7.50(dd, IH), 7.55(td, IH), 7.63(d, IH), 7.72-7.81(m. 3H). 7.86(dd, IH), 8.22(dt,
IH), 8.53(s, IH), 8.64-8.66(m, IH).
2- (2-5^T/:7a:-;0 -4- (3-fcfU5?;i') -6- (2-trU5?;W -3
(2ii) -lfU:$^>^y>
iH-NMR(400MHz, CDCI3); 6 (ppm) 7.37(ddd, IH), 7.42(ddd, IH), 7.44-
7.62(m. IH), 7.78-7.83(m, 3H), 7.88(dt, IH). 8.22(dt, IH). 8.35<ddd, IH), 8.67-
8.71(m, 3H), 9.12(dd, IH).
|li&«»J4 6
2- i2-~^7yy:'^=^M -4- (2->'Ty7ai-JV) -6- (2-^:!'Jv?JW
-3 (2H) -tfUy>?/>
iH-NMR(400MHz, CDCI3); 6 (ppm) 7.35(ddd, IH), 7.54-7.60(m, 2H), 7.70-
(J 7.89(m, 7H), 8.24(d, IH), 8.65-8.67(m, IH), 8.71(s, IH).
^*aj4 7 . -
4- (2-^u=Ey3L-)V) -2- (2-$^Ty73in;i') -6- (a-tfus^;!/)
-3 (2Jf) -t!U^>^y>
>H-NMR(400MHz, CDCI3); 6 (ppm) 7.32-7.S9<m, 2H), 7.49-7.^9<m, 3H),
7.68(td, IH), 7.74-7.82(m, 4H), 8.14(dt, IH), 8;€5-8.67(m, IH), 8.7 l<s, IH).
|liS^^4 8
2- (2-i^Ty7xr:jl.) - 9 -:7;i':tn- 4 -^x-JW- 2 . 3. 4, 4 a-
85
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7=-h^kKD-5/f- (1) ^>V'tr^y [4. 3-c] \£0^i^>-S-:t>
iH-NMR(400MHz, CDCI3); d (ppm) 3.66-3.74(m, 2H), 3.90-3.98(m. IH), 4.03-
4.09(m, IH), 6.88(dd. IH), 7.04(ddd, IH), 7.28-7.33(m, 2H), 7.35-7.49(m, 4H),
7.64-7.77(m. 4H).
2- (2-e^7/:7ai-;W) -4- (3-fc'Uv?;V) -2. 3, 4,. 4a-5^h^
tFP-5if- (l>^>\/t:^y [4. 3-c] fU i5^S^>- 3 -:t>
iH-NMR(400MHz, CDaa); 6 (ppm) 3.66-3.80(m, 2H), 3.97-4.10(ni, 2H), 6.91-
6.95(m, IH), 7.00-7.06(m, IH), 7.32-7.37(m, IH), 7.41-7.51(m, 2H), 7.66-7.79(in,
4H), 8.01-8.06(m, IH), 8.50-8.53(m, IH), 8.64-8.68(m, IH).
2- (2->^D^:7ji-;1') -4- (3-tr'j5?;W -2, 3. 4. 4a-7^h^
tFn-5if- (1) ^>yH^y [4. 3-c] \£V^z^>-Z-^>
^H-NlVIR(400MHz, CDCI3) ; 6 (ppm) 3.64-3.77(m, IH), 3.93(d, IH), 4.01-
4.12(m. 2H), 6.94(d, IH), 6.98-7.04(m, IH), 7.28-7.38(m, 2H), 7.42-7.S8(m, 2H).
7.66-7.74(m, 2H), 7.98(dd, IH), 8.01-8.07(m, IH), 8.67-8.74<m, 2H).
5 1
2- {2--fu^yjL-M -4- (2-t Fn^->:7 3inj0 -6- (2-H'J
>^)u) -3 (2JJ) -tfuy5^y>
»H-NMR(400MHz, CDCI3); 6 (ppm) 7.04-7.09(m, 2H), 7.35.7.45(m, 3H),
7.54-7.59(m, 3H), 7.76.7.81(m, 2H), 8.17(dt, IH), 8.67-8.71(m. lH),«.79(s, IH),
9.36(s, IH).
His^^i 5 2
2- (2->'*D^7:c-Jl') -4- (4-^ >^>':7ac:-JW -6- (2-tfUS^
;i/) -3 (2ii) -k-u^i^y>
^H-NMR(400MHz, CDCI3); 5 (ppm) 3.86(s, 3H), 6.98(d, 2H), 7.31-7.38(m, 2H),
7.48-7.56(m,-2H). 7.73-7.78(m, 2H), 8.04(d, 2H), 8.14(dt, ffi), 8.60(s, IH). 8.67-
86
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8.68(in, IH).
2_ (2->>Ty7x-;W) -9->';i/:to-5-kh*P^">-4-7a::::;l/-2.
3— :?kHD-5H- (1) '^^l/tf^y [4. 3-c] trU^i^>-3-:i->
iH-NMR(400MHz, CDCl^; 5(ppm) 3.61(d, IH), 6.10(d, IH), 7.01<dd, IH),
7.07-7.14(m, IH). 7.47-7.54(ni, 3H), 7.54-7.66(in, SH)^ 7.72-7.80(in, 3H), 7.83-
7.88(m, IH).
Hifi^J 5 4
2- (2->'Ty7x:^;i') - 9-7;l':ta-4-73i— ;i'-2, 3->?t FD-
5H- (1) -^>yt:7/ [4, 3-c] t?'J^e^>-3-:t>
iH-NMR(400MHz. CDCI3); 5 (ppm) 5.09(s, 2H). 6.96(dd. IH), 7.02-7.09(m, IH),
7.37-7.43(m, 2H), 7.45-7.60(in, 4H), 7.72<dd. IH), 7.74-7.79(in, 2H), 7.86(d. IH).
^B^fd 5 5
2^y:sLZL)v-e- (2-t!Ui^;w -4- (2 - hu :7;^:ta;^5^;^x;^^::^-'^
iH-NMIl(400MHz, CDCI3); <5 (ppm) 7.33(ddd, IH), 7-41-7;45(m, 2H). 7.49-
7.55(m, 4H). 7.65(dd. IH), 7.73-7.55(m. iH). 7.79(dt. lED, 8.21(td, IH), 8.-57(s.
IH), 8.65(ddd, IH).
SIS£«»J 5 6
2- (2-7*0^7xli;i.) -4-7aiIi;i^-6- (2-trU>^;W -3 (2ii)
»H-NMR(400MHz, CDCI3); 5 (ppm) 7.32(ddd, IH), 7.36(ddd, IH), 7.44-7.50(m,
4H), 7.54(td, IH), 7.73-7.78(m, 2H), 7.99-8.01(m, 2H), 8.14(dt, IH), 8.65(8, IH),
8.66-8.68(in, IH).
^iS«^J 5 7
2- (2-^0^7x^)1/) -4- (3-t:'J>?;W -2. 3-S^kHP-5iJ-
(1) ^>V}^yy [4. 3-c] tfU;5^i^>-3-:^>
^H-NMR(400MHz, DMSO-de); 6 (ppm) 5.12-5.28(m, 2H), 7.06-7.15(m, 2H),
87
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7.43(ddd, IH), 7.49(ddd. IH), 7.55-7.64(m. 2H), 7.71(dd, IH), 7.84-7.93(m, 3H),
8.64(d, IH), 8.68(dd. IH).
IIJS««1 5 8
2- (2-3-H7x:=:;P) -4- (3-tfU>^;W -2. 3->?fc:Ha-5J/-
(1) ^>\/tf^y [4. 3-c] tfU:$^i?>-3-:^->
^H-NMR(400MHz, DMSO-dg); 6 (ppm) 5.15-5.28(in, 2H), 7.06-7.l6(m, 2H),
7.27-7.33(m. IH). 7.40-7.46(m; IH), 7.55-7.67(ni, 3H), 7.86(dd, IH). 7.90(ddd. IH),
8.06(dd, IH), 8.64(d, IH), 8.69(dd, IH).
lliSlfil5 9
2-:7in;W-4- (S-tfUv^;!/-) -6- (2-t!Ui?;i/) -3 (2*f) -fcfU
iH-NMR(400MHz, CDCI3); 5 (ppm) 7.35(ddd, IH), 7.40-7.48(m, IH), 7:62-
7.56(m, 2H), 7.71-7.75(m, 2H), 7.80(td, IH), 8.20(dt, IH), 8.37(dt, IH), 8.67-
8.69(nx. 3H), 9.12(d, IH).
4- (2-:/o^rr7x-;i/) -2->'x-;i/-6- (s-truv^;!/) -3 (2^0
»H-NMR(400MHz, CDCI3); 5 (ppm) 7.27-7.53<m, 7H), 7.69(dd, IH), 7.77-
7.81(m, 3H), 8.22(dt, IH), 8.47(s, IH), 8-63-8.65<m, IH).
2- (2->^o^::7x-;p) -4- (3-tfu>';0 -6- (2-t!'J>^;i') -s
»H-NMR(400MHz, CDCI3); 5 (ppm) 7.33-7.42(m, 3H), 7.52(td, IH), 7;5«(dd,
IH). 7.77(td, 2H). 8.15(dt. IH), 8.18(dt, IH), 8-67-6.€9(m, 2H), 8.72(s. IH),
9.15(dd, IH).
6 2
2- (2-:i7nnr7x— ;v) -4- (4-^;i':^u >'x^;i/T5y*;i^3ii^— ;i/) -
6-:7x::i;u-3 (2ii) -fcfuye^y>
88
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^H-NMR(400MHz, CDCI3); 6 (ppm) 2.45-2.64(m, 6H), 3.58-3.76(m, 6H), 7.46-
7.53(in, 6H). 7.59.7.63(m, IH), 7.86.7.91(ni, 2H), 8.84(s. IH), 9.64(brs, IH).
2_ (2--hO>'3^-;P) -4- (3-t!'Ji?;V) -6- (2-t!'Ji^;i') -3
2- o-tfUv';^ -4- (2-tfu>^;w (loomg)
^l-Zf^y-)^ (5ml) (C^^U, 2-3zhD:7xn;i/t:H^>^> (6 Omg)
«Fb-i!ftini^iSSi£Lfc. Bit^e^mx5^;vT?^u. m
Omg) ^mzo
iR-NMR (400MHz, CDCI3) ; 6 (ppm) 7.34-7.42 (m, 2H), 7.66 <ddd, IH), 7.74-
7.85 (m, 3H). 8.10 (ddd. IH). 8.17 (dd. IH). 8.32 (ddd. IH). 8.67-8.71 (m, 2H), 8.72
(s, IH), 9.10 (dd, IH).
2- (3-h;w;W -4- (3-tf'J>?;W) -6- (2-HU>^;V) -3 (2/i)
64-1) 4- (S-lfUS^;!-) -6- (2-tfU-:?;W -4. 5-5^.tHa-3
(2ii) -if»ji5^>^y>
2- (S-tfUv^;!-) -4- (2-fcfU>^JU) -4-:t^ySS^ (1. 88g)
^JL^y-}V (4 0ml) t K^>^>-7KfP«^ (0. 3 7g) -^m-
:ij^Ai57 0-7hif^7^-(p^^y-J^-iJ7DD3jN;i'A)-tr»Mb> ^^ib^^ (1.
7 7 g) ^ntco
^H-NMR (400MHz, CiDCla) ; 6 (ppm) 3.45 (dd. IH), 3.71 (dd. IH), 3.88 (dd, IH),
89
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7.27-7.34 (m, 2H), 7.66 (ddd, IH), 7.76 (ddd, IH), 8.05 (ddd, IH), 8.55 (dd, IH),
8.57-8.62 (m. 2H), 8.78 (br s, IH).
64-2) 2- (3-h;W;W -4- (3-tfU>^;P) -6- (2-t!U>^Jl')
-3 (2/i) -lfUjS^>^/>
4- (3-tiUi^;W -6- (2-tfU5^;i') -4. 5-5^kHO-3 (2/i)
_tfij>5fi?y > (5 0mg) ^N. N->';<5^;1/3}n;1/AT5 K (2ml) tC^^U,
in_h;i,-f;j,3j^D>®? (5 4ing) > hUx5^;i'TS> (0. 0 6inl) 43<tZ^
mm (7mg) ^laiwX— M^«#b}fco sf&^^s^^x5^;i/-e^$Rb,
i^M-fk^i^ (lOmg)
^H-NMR (400MHz, CDCI3) ; 5 (ppm) 2.46 (s, 3H), 7.26-7.30 (m, IH), 7.35 (ddd,
IH), 7.38-7.45 (m, 2H), 7.47-7.54 (m, 2H), 7.80 (ddd. IH), 8.20 (ddd, IH), 8.36
(ddd, IH), 8.66 (s, IH), 8.67-8.70 (m, 2H), 9.10-9.12 (m, IH).
l&iB|IJ£««J6 4^mCD^Slc:2pi;Titi£«SI6 5 73M6 9 (D^^Mit^^^-^^l^
Hifi^fiJ 6 5
2_ (4-p^iS/>x;i'3i^x;i/:7aix;i/) -4- (3-if'J>^;i') -6- (2-tfU
i^)V) -3 (2iJ) -tfU^>^y>
»H-NMR (400MHz, CDCls) ; 5 (ppm) 3.12 (s, 3H), 7.40 (ddd, IH), 7.43 (dd, IH),
7.84 (ddd, IH), 8.02-8.07 (m, 2H), 8.10-8.15 (m, 2H), 8.20 (d, IH). 8.32 (ddd, IH),
8.69-8.73 (m, 3H), 9.11 (d, IH).
6 6
2- (4-t*:7xX;P) -4- (3-tfU>?;W -6- (2-t:U>^;W -3 (2
ii) -\f^j^s^y>
^H-NMR (400MHz, CDCl^ ,6 (ppm) 7.34-7.44 (m, 3H), 7.46-7.51 (m, 2H),
7.63-7.68 (m, 2H), 7.73-7.77 (m, 2H), 7.79-7.84 (m, 3H), 8.24 (dd. IH), 8.37 (ddd,
IH), 8.68-8.71 (m. 3H), 9.13 (d, IH).
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2- i2-ry^)V) -4- (3-lfUi^;i/) -6- (2-HUi?;V) -3 (2fJ)
^H-NMR (400MHz, CDCI3); d (ppm) 7.36 (ddd, IH), 7.42 (dd. IH), 7.53-7.60 (m,
2H), 7.78-7.86 (m, 2H), 7.90-7.96 (m, 2H), 8.00 (d. IH), 8.22-8.27 (m, 2H). 8.38
(ddd. IH), 8.68-8.73 (m, 3H), 9.14 (d, IH).
2- (3, 4-^^l/>v':^=^'>7a:-;k) -4- (3-t!Ui^;W -6- (2-
^H-NMR (400MHz, CDCls) ; «5 (ppm) 6.07 (s, 2H), 6.93-6.96 (m, IH), 7.17-7.21
(m. 2H). 7.36 (dd, IH), 7.41 (dd, IH), 7.80 (ddd, IH), 8.18 (d, IH), 8.34 (ddd, IH),
8.65 (s, IH), 8.67-8.71 (m, 2H), 9.11(d, IH).
2- (3, 4->?i7DD>'3i— ;W) -4- (3-tfUv;W -6- (2-fcfU>^;W
-3 (2H) -\^nyi^y>
^H-NMR (400MHz, CDCla),- 6 (ppm) 7.38 (ddd, IH), 7.42 (ddd, IH), 7.60 (d, IH),
7.68 (dd, IH). 7.83 (ddd, IH), 7.93 (d, IH). 8.19 (ddd. IH), 8.32 (ddd, IH), 8.67 (s,
IH), 8.68-8.72 (m, 2H), 9.08 (d, IH).
IIJg*»J7 0
2- (.2-i^7yy:^=-}V) -4-7ai::i;U-6- ( 2 - tf U S i^^l') -3 (2 /J)
4-y:jL=.)V-6- (2-k-U5>^;V') -3 (2H) -tfUi$^5^y> (10 0m
g) ^1i'ft;'^^l/> (5ml) \zmmiy^ 2- (2— >Ty7ai-;W -1. 3.
2_e?:a-4^i^-7i?U^--b (0. 2 2g). fcrU5?>(0. 1 0 g) -^.fcU^m^ (0 .
1 5g) ^MTi^ Mi^^zx-Mi^mwvt^o Kft^m^mit:^^u>-^^^>
ti^'ft:#4^ (2 9mg) ^^;feo
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iH-NMR (400MHz, CDCi^ ; 6 (ppm) 7.37(dd, IH), 7.46-7.63(m, 3H), 7.57(ddd,
IH), 7.72-7.80(m, 2H), 7.84(dd, IH), 7.95-8.00(m, 2H), 8.70(s, IH), 8.92(d, 2H).
mmmi i
3 (2if) -trut$^e?y>
iH-NMR (400MHz. CDCI3) ; (5 (ppm) 3.89(s. 3H), 6.98-7.04(m, 2H), 7.31-
7.42(m. 4H), 7.62(dd, IH), 7.68(dt, IH). 7.78(ddd, IH). 7.91(ddd, IH). 8.70-
8.73(m, 3H).
^:^^J7 2
2- {3-^^)V^}Vyj^=^)V) -4- (S-lfUv^Jl-) -6- (2-l:f'J>^;V') -
3 (2ii) -tf'J:$'*i^7>
iH-NMR (400MHz, CDCI3) ; 6 (ppm) 7.37-7.44(m, 2H), 7.72(t, IH). 7.83(dt,
IH), 7.98(td, IH). 8.08(ddd, IH). 8.21(td, IH), 8.30-8.36(m. 2H), 8.69-8.72<m,
3H), 9.10-9-12(m, IH), 10.11(s, IH).
^iS^J7 3
2_ (5-^7x>-3-'f;V) -4- (3-lfU>^;i/) -6- (2-H'J5?;W) -
3 (2/£) U:$'*-:^y >
»H-NMR (400MHz, CDCI3) ; 6 (ppm) 7.36-7.44(m, 3H), 7.77(dd, IH), 7.82(ddd,
IH), 8.20(dd, IH). 8.26(td. IH), 8.32(ddd, IH). 8.61<s. IH), 8.68-8. 7 l(m, 2H).
9.08(dd, IH).
7 4
2- (3-t°ue?;i^) -4-7x-;i^-6- (2-tfu>»;i') -3 (2fi) -fj
^H-NMR (400MHz. CDCI3) ; 6 (ppm) 7.36(ddd. IH), 7.44-7.52(m, 4H), 7.82(dt.
IH). 7.92-7.95(m, 2H). 8.18-8.22(m, 2H), 8.63(s. IH), 8.66(dd. IH), 8.69(ddd, IH).
9.06(d,lH).
92
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^H-NMR (400MHz, CDCI3) ; 6 (ppm) 7.38(t, IH). 7.44-7.52(m, 4H), 7.94-
7.96(m, 2H), 8.11(ddd, IH), 8.64(s,lH). 8.67(dd, IH), 8.93(d, 2H), 9.02(dd, IH).
^mm 7 6
2- (2-^h^5^:7:cri;i.) -4- (S-tfUi^Jl-) -6- (2-liUv^;W -
4. 5-5?t:Hci-3 (2iJ) -trU^S?/>
^H-NMR (400MHz, CDCI3) ; 6 (ppm) 3.56-8.88(m, 5H), 4.10(t, IH), 7.00-
7.07(m, 2H). 7.25-7.29(in, 2H), 7,34-7.40(m, 2H), 7.67(dt, IH), 7.75-7.80(in, IH).
8.05(td, IH), 8.52(dd, IH), 8.60(ddd. IH), 8.65-8.69(m, IH).
^JS^^J 7 7
»H-NMR (400MHz, CDCI3) ; 6 (ppm) 1.70(s, 31^, 3.11(d, IH), 3.7-2(d, IH),
7.22-7.30(m, 4H), 7.33-7.36(m, 2H), 7.38-7.42(m, 5H), 7.«3-7.S7(m, 2H), 7.75-
7.78(m, 2H).
mmm i s
2_ (2-^a^:7ai-;i/) -4-^5^;i'-4, 6-i>7x— ;P-4, S-S^tlF
D-3 (2Ji) -tru3^>^/>
iH-N»lB (400MHz, CDCI3) ; 6 (ppm) 1.73(s, 3H), 3.17(d, IH), 3.75(d, IH),
7.22-7.25(m, 2H), 7.28-7.32(m, 2H), 7.36-7.42(m, 7H), 7.64-7.68(m. 2H). 7.72-
7.78(m, 2H).
2- (3-t°US^>- l-^^->H) -4-:7i-;i/-6- (2-fc:Ui^;V) -3
(2fJ) -tfU^>^y>
2- (S-tfUi?;!/) -4-7a.::i;i'-6- (2-tfUS^JW -3 (2JJ) — f
93
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(2 2 4mg) <h-Ji? uu :^^ymil (5nil) tc. %W^. 7 0%:/^
^-'!7Uum^B.mm (1. 2 7g) l^F^m^bfeo 2N7km<b
(1 1 7mg)
^H-NMR (400MHz. CDCla) ; 6 (ppm) 7.38-7.42<m, 2H), 7.48-7.52(m, 3H),
7.84(dt. IH), 7.89-7.91(m, 2H), 7.99(ddd, IH), 8.21(td, IH). 8.25(ddd, IH), 8.€2(s,
IH), 8.69(ddd, IH), 8.84(t, IH).
HiS^JSO
BOA) 2- (2— >T/i;US^>-5-^;W) -4-:7a^r:;V-€- (2-tfU
-3 (2ii) -trUi5^v^/>
BOB) 2- (2-->T/tf U5?>-3— f;!--) - 4 -:7xr:;i/- 6 - (2-t!U
5^;v) -3 i2H) -fu^'v'yv
2- (3-t;'J>'>-l-:=r^~>K) -4-:7x-;i'-6- (2-t:U>'JW -
3 (2ii) -tfU^>^/> (5 2ing) 07-t hnhUJl' (2m 1 ) . i^UU-is)V
A (2ml) m^^mmiZ. i^TyhV/>^)Uz^^> (0. 12nil) S:tKhUX^
;WT5> (84/zl) — IlfeiPi^BStSbfc.
T^t^b. *|-fe@#02- (2-->T/HUe?>-5 — f)V) - A-y 3lZ1}V- Q
- (2-t:U>^;V) -3 (2fJ) -tf'J^'i^y > (2 4mg) t||fe®#:<D2- (2
-v-Ty tfUi^>-3— r;w -4-73i-;w-6- (2-fcfu>';w -3 (2fi)
-trU^>^>'> (12mg)
BOA;
^H-NMR (400MHz, CDCI3) ; 6 (ppm) 7.40(ddd, IH), 7.49-7.52(m. 3H), 7.83-
7.92(m, 4H), 8.19(td, IH). 8.64(s, IH), 8.70(ddd. IH). 9.27(dd, IH).
8 0 B;
^H-NMR (400MHz. CJDCla) ; 6 (ppm) 7.38(ddd, IH), 7.48.7;52(m, 3H),
7.70(dd, IH), 7.82(dt, IH), 7.93-7.95(m, 2H), 8.22(dd. IH), 8.26(td, IH), 8.66(s,
94
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IH), 8.69(ddd, IH), 8.79(dd, IH).
mmm si
8 1A) 2- (2-v'Ty b°Ui^>-5-'f;i') -4-73i— ;W-6- (2-t:»J
S.z^)V) -3 (2iJ) -tfUt5^e?>'>
BIB) 2- (2->'7y k!'j>^>-3— -4-7i— ;l'-6- (2-fcfU
BtilB^iS^SJ 80tl^^l'UT2-(2-->Tyt:Ui^>-5-<;V)-4->'ai
-;i.-6- (2-lfU52^;W -3 (2iJ) - 1: U iJ^'S^/ >*5cfctX2 - (2-->T
y trU5^>-3— f;!') -4-7a:-;W-6- (2-tfU5>?;W) -3 (2ii) -
8 1A;
^H-NMR (400MHz. CDCI3) ; 6 (ppm) 7.42(t, IH). 7.'5d-7.54<m, 3H), 7.85(dd,
IH), 7.91-7.93(m, 2H), 8.37(dd, IH), 8.63(s, IH), 8.94(d, 2H), 9.23(dd, IH).
8 1 B ;
^H-NMR (400MHz. CDCl^ ; 6 (ppm) 7.40(t, IH), 7.49-7.S2(in, 3H), 7.71(dd,
IH), 7.95-7.97(in, 2H), 8.12(dd, IB), 8.71(s, IH), 8.79(dd, IH). 8.93<d, 2H).
|lliSfi«J 8 2
2- (2->^Ty7x^;W -4-7x-;W-6- (2-tf^5^;W -3 (2fJ)
6-i^DD-2- (2-5/Ty73in;W -4-7ai::^;i'-3 (2H) -k*U^
$?y> (16mg) . 2- hUy5=-;i/X37— ;i't!^>^> (2 5ing) , T^h^^:^
(hU:7x:n;i'3l^:5^7W» nv^-^^h. (3mg) Sr^5^lx> (1ml) icsnA.
^^^H^T. 12 0'CT2^r5iti*Ufc. SjS?g^^«NH->"J:^jer;v:^3^A
g) ^#fcc
^H-NMR (400MHz, CDCI3) ; 5 (ppm) 7.45-7.62(m, 4H), 7.78-7.80(m. 2H),
7.88-7.96(m, 3H), 8.54(s, IH), 8.62.8.64(m, 2H), 9.45(d,2H).
|lti£«»J8 3
95
wo 02/22587
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2- i2~=yy J-P:suZL)V) - 4 -y :c:z.JV- 6 - {^T'/-JV-2 — (M -3
»H-NMR (400MHz, CDCI3) ; 6 (ppm) 7.47-7-50(in, 4H), 7.59(ddd, IH), 7.75-
7.81(m, 2H), 7.87(ddd, IH), 7.92-7.95(m, 3H), 8.40(s, IH).
mmm 34
»H-NMR (400MHz, CDCl^ ; 6 (ppm) 1.75(s, 3H). 3.21(d, IH), 3.74(d. IH),
7.25-7.27(in, IH), 7.29-7.34(m, 2H), 7.37-7.45(m, 6H), 7.57<ddd, IH), 7.66(ddd,
IH), 7.73(ddd, IH), 7.75-7.78(iQ, 2H).
mnM 8 5.
2- (2-:/a^:73c-;W -4- (2 -p^ h^^5^:7a:^;i') -6- (2-tfU>^
;V) -4, 5->^kHa-l. 2, 4-hUT>?>-3 (2ii) -:^>
2- (2-:;^n^:7ain;i^) -6- (2-t!U>?;U) -4. 5-i?tHo-l.
2, 4 - hUT>^>-3 (2iJ) (7 Omg) St^StKt^ h ^ k H D 7 ^ > (1
Oml) t^ML. mfkm (7 7mg) , 7K^-fb:J- h U 'i'A (2 5mg) ^ 2-:<
h4^>':7xr:;i/2|?D>m (7 7mg) ^■m^^t^i^-ci^^M^^'^^o Ti^M^ti-h
\J^A (2 5mg) ^ 2->^h=¥^yaL=.)V:^U>m 5 Omg) ^$6>{CtWA^
S^'fk'&i^ (5 5mg. 6 0%) ^#feo
^H-NMR (400MHz, CDCI3); 6 (ppm) 3.85 (s. 3H), 5.02 (s, 2H). 6.94-6.99 (m,
2H), 7.20-7.31 (m, 3H), 7.35-7.42 (m, 2H), 7.62 (dd, J=7.6Hz, 1.6 Hz, IH), 7.66^
7.73 (m, 2H), 8.09-8.11 (m, IH), 8.54 (ddd. J=5.0 Hz, 1.8 Hz, 1.6 Hz, IH).
96
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2- i2-Z^U=Ey3L-)V) -4- (2-t:Ha:^S^73i-JW -6- (2-HU
z^JV) -4, 2, 4-h<JT-:^>-3 (2Ji)
2- (2-7*D^:7:n-;i.) -4- ( 2 - ^ h^^'>:7a::=i;W - 6 - (2-tfU
yj^) _4, 5-i^th*0-l. 2, 4-h'J7i?>-3 (2fi) (4 8m
g) <oz^^uu^^>m^ (10ml) \z. *?&Tx iM3i?o>hU:/nv-i' HIS
it^^u>mm (o.smi) ^mx. smmm^vr^^ K}^m\zmimmyi^mi-h
6mg. 7 8%) ^mtcLo
m-NMR (400MHz, CDCLOl « (PP™) 5.23 (brs. 2H), 7.02-7.10 (m. 2H), 7.20-
7.36 (m, 4H), 7.46 (td, j=8.0 Hz, 1.2 Hz. IH), 7.62 (dd, J=8.0 Hz. 1.8 Hz, IH),
7.71-7.76 (m, 2H), 8.09 (d, J=8.0 Hz, IH). 8.59 (d, J=5.2 Hz, IH).
ESI-Mass; 423 [M*+H]
^Jfi«^ 8 7.
2- (2->'7y7x-;W -4- (2-^h^>'7a:-;i') -6- iZ-Jd^Jz^
)].) -4. 5-5?tHP-l. 2. 4-hUTS?>-3 (2ii)
2- (2--:/a^r7 3injl/) -4- (2-^ h=¥->:73i-;W -6- (2— tfU
5->^kHO-l. 2. 4-hUTi^>-3 (2/^ (9 9m
g) K (2 0ml) fc^^b, ~>T>'fkm (5 1mg) ^tP
A. 1 5 0'Cl3T3^H«i$bfCo K]t^m^^U^X'}^^Vrzm. T>^-T:dc (2
0ml) t@^S!X5^;i'^JnA. *^S^:«-i2b^ 7lc-eSfe#. |g*?Sfem^hU^7AT'
(^:^-y->-TOx5^;U^) tfilSgib, ^gfiT*;W:7 7X-®«^^k-&*^ (7 2mg,
8 3%) ^#fco"
»H-NMR (400MHz. CDCI3); 6 (ppm) 3.87 (s, 3H). 5.04 (s, 2H), 6.97-7.01 (m.
2H). 7.25-7.39 (m, 4H). 7.61-7.66 (m. IH), 7.72-7.78 (m, 3H). 6.22 (d, J=8.0 Hz.
IH), 8.54 (ddd, J=4.8 Hz, 1.6 Hz, 1.2 Hz, IH).
97
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ESI-Mass; 384 [M^+H]
mmmss
2- (2-:/n^:7xi;V) -4-7ai-Jl/-6- (2-tfU>';W -4, 5-5^
kHa-1. 2,.4-hUT>^>-3 (2ii)
2- (2-:fn^7x-;V) -6- (2-fc!U5?;W -4. 5-5^tHo-l,
2, 4-hU7i/>-3 (2fi) (1 2ing) ^^i7K>';J7 O > (30
ml) ^c:^^b^ KUX5^;^T5> (O.lml) . it^^ (13.2mg) ^ yoL
-}V:^.u>m. (1 3.3mg) ^M7L'm.^\Z.'Z A ^mmmWX^tZo TK^^ki^hU'^A
(Smg) t:7ai— jwjj^o^m (lOmg) ^^^iclni;^. ^iatcTSi^Wit^b
mg, 7 5%)
^H-NMR (400MHz, CDC^v 6 (ppm) 5.15 (brs, 2H), 7.21-7.31 (m, 3H), 7.36-
7.46 (m. 3H), 7.47-7.52 (m, 2H), 7.62 (dd, J=8.0Hz, 1.8 Hz, IH), 7.68-7.74 (m, 2H),
8.10 (dt, J=8.0 Hz, 1.4 Hz, IH), 8.57 (ddd, J=5.0 Hz, 1.8 Hz, 0.8 Hz, IH).
ESI-Mass; 407l]Vr+H]
mmm 8 9
2- (2-:/a^::7i-;i/) -6- (2 -p^ h^r->:7ac— ;0 -4-:7i— ;i'-4.
S-v'tHo-l, 2, 4-hUTS^>-3 (2Ji) -:^>
Horst Gnichtel, Widah I. Salem und Lothar Waretschel^ Liebigs Ann. Cbem.
(1978) 2033-2043 ©;^^£fc^leVi£;lT®i5 tCfrolt. 2-yD^-2'-;>^h^
~>y-feh7xy> (1.3 3g) tT:=:u> (1.0 eey^x^^^y-;!^ (2 Oml)
#e.nfc^'fet4«07ir h7iy>^S#: (l.l2g) ^XiJ^y-^U (20ml)
^3^^b^ 2-:/n^7aix;i't H^i?> (9 3 0mg)^jbnA"r, ^latcT— nfe
^i^bfe. SJ«:^^MBETii«gU WM. (1.8 4g) $xh^-kKP7^> (2 0
98
wo 02/22587
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ml) 7K?&T. hV^7.y> (4 5 9mg) tbUx5^;VT^> (1-
4ml) ^m^.^^^^\zm.u\z^^vf3i-d^^zm^mnvrco K^M^m.s.rmm
«t^T^:;V7 77.®^^fb-&i^ (4 3 8mg. 17%) ^^fCo
^H-NMR (400MHz, CDCJla); 6 (ppm) 3.87 (s. 3H), 4.85 (s, 2H), 6.92 (d, J=8.4
Hz, IH). 7.01 (t, J=7.4Hz, IH), 7.18-7.25 (m, 2H), 7.27-7.46 (m. 6H), 7.64-7.68 (m,
2H), 7.71 (dt, J=7.6 Hz, 1.6 Hz, IH).
ESI-Mass; 436 DVr+H]
llliS«»l9 0
2- (2-ya^7aL-;W -6- (2-tHO^->7aiX;i/) -4-7ai-;V-
4, 5-v^tFn-l. 2. 4-hUT>^>-3 (2fi) -:^>
mmm8 6izmm<o:^mzmvx2- C2-':rn^y3L=i}v) -e-
^ft-v-:?:!!-;!^) -4-:7x-;i'-4. 5-i^th*o-i, 2. 4-bUTe?>-3
(2H) -:r>'.(l 4 7mg) A^^MS^t-^^ (1 3 5mg, 9 5%) €:#fCo
^H-NMR (400MHz, CDCaa); « (PP™) 4.98 (s, 2H), 6.91 (t, J=8.0 Hz, IH), 7.00
(dd, J=8.0 Hz, 0.8 Hz, IH), 7.25-7.35 (m. 4H), 7.40-7.48 (m, 5H), 7.58 (dd, J=8.0
Hz, 1.6 Hz, IH). 7.69 (dd, J=7.8 Hz, 1.4 Hz, IH), 10.96 <s, IH).
ESI-Mass; 424 [M*+H]
mnm 9 1
2- (2-7*0^7iX;l') -6- (2-i:^;<5^Jl'T5yxh^>':7 3:X;W -4
_-7^-;i,_4, 5—:?th*D-l. 2. 4-hUT>'>-3 (2iJ)
2- (2 -:/n^7xx;i') -6- (2 -t Fo^v'7xx;p) -4-:7 3ix;i^
-4, S-v'th'O-l. 2, 4-bUT>'>-3 (2ia) -:^> (1 0 0 mg)
^s^^5^;^7^^;^AT^ H (2 0mi) i^mj^'J^^A (6 6mg) ^ia^.
Ai^D-Th^^^-f- (^^t^>-B^mx5^;^^) •^^SSL--
99
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#1 (6 5mg, 5 5%) ^nt:io .
^H-NMR (400MHz, CDCI3); d (ppm) 2.26 (s, 6H), 2.65 (t, J=5.8 Hz, 2H), 4.11
(t, J=5.8 Hz, 2H).. 4.93 (s. 2H), 6.91 (d, J=8.0 Hz, IH), 6.98 (td, J=7.6 Hz, 0.8 Hz,
IH). 7.16-7.25 (m, 2H), 7.33-7.39 (m, 3H), 7.40-7.46 (m, 3H), 7.66 (td, J=8.0 Hz.
1.6 Hz, 2H), 7.72 (dd, J=7.8 Hz, 1.8 Hz, IH).
ESI-Mass; 495 (M*+H]
2- (2->^Ot7a:^;i') -6- ( 2 h^v'^oi— ;i') -4- (2-HU>^
;W -4. 5->?fcHa-l. 2, 4-hU75^>-3 (2H) -:^>
mmms stijMs 7tciBm(Z):;&}£tc2pcx'&fiK$ns2- (2-:^a^7x-
;i.) -6- {2->^h^z^yaL=LM -4, 5-i^fcb'a-l, 2, 4-hUT>^
>-3 (2H) -:t> (1 9 3mg) ^>';*5^;^JJ^;^Ai^$ H (2 0ml) i'^^
2-Zfo^i^0z^> (SOOmg) , ^m:^J'J'^A (18 5mg) , S^itM
2 0.4mg) 1 3 O'GTfSB^F^Mbfc. ^ia^-e??r^bfc^. T>^:^
77K (2 Oml) .i:i^mx5^;i^$:J0A. :#^®^^iBU. TK^eifc^. Si7K5iim:M-
(^:^-^^>-g^gtx5^;^5^) TJWiau. mB.'B^<omm<t^i^ (i 2
6 mg. 5 4%)
^H-NMR (400MHz, CDCI3); 6 (ppm) 3.84 (s. 3H), 5.10 (brs, 2H), 6.86-6.97 (m,
3H), 7.14-7.18 (m, IH), 7.29-7.38 (m, 2H), 7.54-7.63 (m, 4H), 7.92-7.95 (m, IH),
8.29-8.31 (m, IH).
ESI-Mass; 437 pvr+H]
2_ (2-i^7y7x-;U) -6- (2-h HD^^^v^^JC-JW) -4-7ai-;P-
4, 5-S?kHa-l. 2. 4-hUT>^>-3 (2H)
^H-NMR (400MHz, CDCI3); <5 (PPm) 5.00 <s, 2H), 6.91-6.96 <m, IH), 7.02 (dd,
wo 02/22587
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J=8.4Hz, 0.8 Hz. IH). 7.27-7.49 (m, 8H), 7.70-7.73 (m. 2H). 7.73-7.77 (m, IH),
10.83 (s, IH).
ESI-Mass; 369 [M*+H]
^ig«3J9 4
2- {2-::^D^::7x-;V') -4- (2, 5-5^1::HD=^>':7ac-;V) -6- (2
-kKo^->7x-;i') -4. 5-e?tHD-l. 2,.4-hUTi?>-3 {2 H)
m-NMR (400MHz, DMSO-dg); 5 (ppm) 4.79 (s, 2H), 6:59 (dd, J=8.8 Hz, 2.8
Hz, IH). 6.70-6.74 (m, 2H), 6.89 (dd. J= 13.2 Hz, 0.8 Hz, 2H), 7.28-7.37 (m, 2H).
7.49-7.57 (m. 2H). 7.66 (dd. J=7.8 Hz, 1.0 Hz, IH), 7.76 (d, J=8.2 Hz, IH), 8.92 (s.
IH), 9.09 (brs, IH), 10.52 (brs, IH).
ESI-Mass; 454 [M*+H]
9 5
4_ (2. 5->?t Ha^v-:7x-;i') -6- (2-t FP^v':7x-;W -2-
7x-;i.-4. 2. 4-h'J75?>-3 (2iJ)
^H-NMR (400MHz, DMSO-d«); 6 (ppm) 4.78 (s. 2H). 6.60 (dd, J=8.8 Hz, 2.8
Hz, IH), 6.70-6.75 (m. 2H), 6.91 (dd, J=12.8 Hz, 7.6 Hz, 2H), 7.23-7.34 (m. 2H),
7.39-7.45 (m. 2H), 7.54-7.61 (m. 3H), 8.92 (s, IH), 9.04 (s, IH), 10.74 (s, IH).
mmm 9 e
2- (2-v'Ty :7x::i;U) -4- (2-b:FD^re^7a:-;i') -6- (2-tru
>^;l/) -4, S-S^tHo-l. 2. 4-hUTi^>-3 (2H) -:t>
^H-NMR (400MHz, CDCJlg),- 5 (ppm) 3.87 (s, 2H), 6.69-6.82 (m, IH), 6.94-7.1C
(m. 2H), 7.22-7.52 (m, 5H), 7.62-7.66 (m, IH), 7.72-7.76 <m, IH), 7.98-8.05 (m.
IH), 8.54-8.67 (m, IH).
ESI-Mass; 370 [M*+H]
Hifi^j 97
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2— i^2-=yy J-y:z.::.}V) -6- (2 h=^£/:73i-;i/) -4-73i-;i/-4.
5->?tHP-l, 2. 4-h'J7':^>-3 (2iJ)
»H-NMR (400MHz, CDCI3); (5 (ppm) 3.87 (s, 3H), 4.86 (s, 2H), 6.93 (d, J=8.4
Hz. IH), 7.04 (td, J=7.2 Hz, 0.8 Hz, IH), 7.20-7.27 (m, IH), 7.34-7.45 (m, 6H),
7.65 (td, J=7.8 Hz, 1.6 Hz, IH), 7.71 (dd, J=7.6 Hz, 1.6 Hz. IH). 7.77-7.«l (m, 2H).
ESI-Mass; 383 PVI*+H]
4_ (2-'>Ty :73i:^;W) -6- (2-p^ h^^^v'^x— ;V) -2-:7x::i;i/-4,
5->?tb'D-l. 2. 4-hUTi^>-3 (2H)
^H-NMR (4003V[Hz, GDCa,); 6 (ppm) 3.85 (s, 3H), 4.85 (s, 2H), 6.90-6.94 (m.
IH), 6.99-7.06 (m, IH), 7.20-7.i26 (m, IH), 7.33-7.43 (m, 4H), 7.49-7.62 (m. IH).
7.62-7.77 (m, 5H).
ESI-Mass; 383 [M*+H]
2- (2— >7y7x-;i^) -6- (2-p^ h^'>7xr^;i') -4- (2-lf'J>^
;i.) -4. 5->^tHa-l. 2. 4-hUT>?>-3 (2iJ)
^H-NMB (400MHz, CDCI3); a (ppm) 3.91 (s, 3H), 5.21 (s, 2H), 6.95 <d, J=8.4
Hz, IH), 7.00-7.08 (m, 2H), 7.39-7.44 (m, 2H), 7.64-7.80 (m, 5H), 7.98-8.01 (m,
IH), 8.39 (ddd, J=4.8 Hz, 1.8 Hz, 0.8 Hz, IH)
ESI-Mass; 384 [M^+H]
Hlffi^ffll 0 0
2- (2-'>T/:7x-;i<') -4-7x-;U-6- (2-trU:^;i') -4.
hHD-1, 2, 4-hUT>'>-3 (2H) -:t->
^H-NMR (400MHz, CDCI3); 5 (ppm) 5.17 (s, 2H), 7.24-7.33 <m, 2H), 7.38-7.44
(m, 3H), 7.46-7.50 (m, 2H). 7.65-7.69 (m, IH), 7.74-7.79 (m, 3H), 8.19-8.22 (m,
IH), 8.57 (ddd, J=4.8 Hz, 1.6Hz, 0.8 Hz, IH).
ESI-Mass; 354 PVT+H]
^»J1 0 1
102
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2- (2-->Ty:7 3i-;W -6- (2-tiUv;W -4- (5^;t7:i:>-3— r
jl,) 5->?t:Ha-l. 2, 4-hU7i^>-3 (2Ji) -^y
m-NMR (400MHz, CDCI3); 5 (ppm) 5.19 (s, 2H), 7.28-7.35 (m, 3H), 7.43 (td,
J=7.6 Hz, 1.2 Hz, IH). 7.47 (dd. J=5.2 Hz, 1.6 Hz, IH), 7.66-7.79 (m. 4H), 8.19 <dt,
J=8.0 Hz, 1.0 Hz, IH), 8.59-8.61 (m, IH).
||»J 1 0 2
2- (2->^7y:7ai-Jl') -6- (2-tfU>';W -4- (2-fU5^;W -4,
5-$^kHn-l. 2. 4-hU75^>-3 (2if) -:^>
^H-NMR (400MHz. CDCI3); 5 (ppm) 5.47 (s, 2H), 7.10 (ddd, J=7.0 Hz, 4.6 Hz,
1.0 Hz, IH), 7.30-7.34 (m, IH), 7.38-7.52 (m, 2H), 7.64-7.79 (m, 4H), 7.99-8.01 (m.
IH). 8.18 (dd, J=8.0 Hz. 0.8 Hz, IH). 8.47-8.49 (m, IH), 8.64-8.66 (m, IH).
ESI-Mass; 355 [M*+H]
HJig^ 10 3
2_ (2->^T/:7 3:::iJW -6- (2-tfU>?;W -4- (S-trUi^JW -4.
S-v^kHo-l. 2, 4-hU7>^>-3 (2iJ) -:r>
^H-NMR (400MHz, CDCI3); (5 (ppm) 5.22 (s, 2H), 7.32-7.38 (m, 2H), 7.44 (td,
J=7.6 Hz, 1.2 Hz. IH), 7.70 (td. J=7.4 Hz, 1.6 Hz, IH), 7.74-7.80 (m, 3H), 7.88
(ddd, J=8.4 Hz. 2.8 Hz, 1.2 Hz, IH). 8.19 (d. J=8.0 Hz, IH). 8:50-8.53 (m, IH),
8.59 (ddd, J=4.8 Hz, 1.6 Hz, 0.8 Hz, IH). 8-78-8.82(m, IH).
ESI-Mass; 355 \M*+B]
m^mm s a tm(D-^mizm\:^'cmmm i o 4 t^m m (oimmit^m^^
mmm 104
4- (2->'Ty:7 3in;w - 2 -:73:ii;v- 6 - ( 2 - tf U -4. s-e^
hKD-l, 2. 4-hUTi?>-3 (2ii) -:a->
^H-NMR (400MHz, CDCI9); 6(ppm) 5.15 (s, 2H). 7.21-7.33 (m, 2H). 7.36-7.46
(m. 3H), 7.52-7.57 (m. IH), 7.65-7.79 (m, 5H), 8.18 (d, J=8.4Hz, IH), 8.54-8.66 (m,
IH).
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ESI-Mass; 354 [M'^+H] '.
2-73L=.)v-Qr (2-ifUi?;i') -4- (5^:^:7a:>-3— r;0 -4, 5-
>^tHo- l. 2. 4-hUT5^>-3 (2 /J)
^H-NMR (400MHz. CDCI3); 6 (ppm) 5.14 (s, 2H), 7.24-7.28 (m, IH), 7.28-7.34
(m, 3H), 1A2-1A1 (m. 2H), 7.50 (dd, J=5.2 Hz, 1.2 Hz, IH). 7.62-7.65 (m, 2H).
7.76 (td, J=7.8 H,z 2.0 Hz, IH). 8.16 (d, J=8.0 Hz, IH), 8.59-8.61 (m, IH).
ESI-Mass; 335[M*+H]
^Jfi««Jl0 6
2- (2-:/o^:7x-;i/) -e- (2-tr'j>?;i/) -4- 73i>-3— f
_4, 5-5^tKP-l. 2. 4-hUTe?>-3 (2ii) -;r>
^H-NMR (400MHz, CDaa); 5 (ppm) 5.18 (brs, 2H), 7.24-7.32 (m, 4H), 7.45 (t,
J=7.6 Hz, IH), 7.52-7.54 (m, IH). 7.59-7.61 (m, IH), 7.69-7.74 (m, 2H), 8.08 (dd,
J=7.8 Hz, 1.0 Hz, IH), 8.59-8.61 (m, IH).
ESI-Mass; 415 [M*+H]
4_ (2. 4-v^p^h=^~>:73i-;v) -2-yaL=L)v-b- (2-true^;0 -4,
5--:^bFn-l, 2, 4-hUT>^>-3 (2fJ)
^H-NMR (400MHz, CDCI3); 6 (ppm) 3.82 (s, 3H), 3.83 (s, 3H), 4.96 -(s, 2H),
6.49 (dd, J=8.4 Hz, 2.8 Hz, IH), 6.53 (d, J=2.8 Hz, IH), 7.20-7.23 (m. 3H), 7.36-
7.42 (m, 2H), 7.66-7.67 (m, 2H). 7.75 (td, J=8.0 Hz, 1.6 Hz, IH), 8.18 (d, J=8.4 Hz,
IH), 8.54 (d, J=4.8 Hz, IH).
ESI-Mass; 389 [M*+H]
10 8
2- (2 -:7*a^:7ac-;i/) -6- (2 h^>':7x:^;V) -4- (g^:^:7x>
-3— f;i/) -4, 5->ftHD-l. 2, 4-hUT-:^>-3 i2H)
»H-NMR (400MHz, CDCls); 5 (ppm) 3.92 (s, 3H), 4.89 (s, 2H), 6.95 (d, J=8.4
Hz, IH), 7.10 (t, J=7.6Hz, IH). 7.14-7.16 (m, IH), 7.21-7.29<m. 3H), 7.38-7:62 (m;
104
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3H), 7.62-7.64 (m, IH), 7.67-7.70 (m, IH).
mmm 109
2_7:c^;i,-6- (2-HU5^;i') -4- (3-l^Uv?;W -4. 5-->t:HD
-1, 2, 4-hUT>^>-3 (2J=J) -:^>
^H-NMR (4001WDBZ, CDCi^; d (ppm) 5.16 (s, 2H), 7.27-7.36 (m, 3H), 7.45 (t,
J=7.8Hz, 2H), 7.63-7.66 (m, 2H), 7.77 (td, J=8.0Hz, 1.8 Hz, IH). 7.86 <ddd, J=8.2
Hz, 2.8 Hz, 1.6 Hz. IH). 8.19 (dt, J=8.0 Hz, 1.0 Hz, IH), 8.48 (dd, J=4.8 Hz, 1.6 Hz,
IH), 8.58 (ddd, J=4.8 Hz, 1.8 Hz, 0.8 Hz, IH), 8.78 (d, J=2.0 Hz, IH).
BSI-Mass; 330 [M^+H]
mmm no
2_ (2-yn^:7i:^;w -6- (2-bfUi^;w) -4- (3-tru>*;i') -4.
5_c?tHa-l. 2. 4-hUTS7>-3 (2H) -it>
^H-NMR (400MHz. CDCI3); <5 (ppm) 5.20 (brs, 2H), 7.26-7.35 (m, 2H), 7.43-
7.48 (m, 2H), 7.60-7.76 (m. 3H), 7.89 (ddd, J=7.8 Hz. 2.8 Hz, 1.4 Hz, IH), 8.10 (d.
J=8.0 Hz. IH), 8.48 (dd, J=4.8 Hz, 1.6 Hz, IH), 8.59 (d, J=4.8 Hz, IH), 8.80 (d,
J=2.4 Hz, IH).
ESI-Mass; 410 [M*+H]
mmm n i
2- (2->^a^:7xn;W -4- (2 — >Ty :7x=.;i/) - 6- (2-fc!'J>^)W)
-4, 2. 4-hUT^>-3 (2/i) -:t>
»H-NMR (400MHz, CDCI3); 6 (ppm) 5.19 (s, 2H), 7.24-7.32 (m, 2H), 7.41<dd.
J=7.6 Hz, 1.2 Hz, IH), 7.45 (dd, J=7.6 Hz, 1.2 Hz, IH), 7.57 (dd, J=8.0 Hz, 0.8 Hz,
IH). 7.64-7.75 (m, 5H), 8.11 (d, J=8.0 Hz, IH), 8.55<ddd, J-5.0 Hz, 1.8 Hz, 0.8 Hz,
IH).
mtmmms9tm(D:^mzmcxmmmi 1275^1 1 7<Dnmit^m^'^
|I»J 112
2- (2->^P^::7x::i;l') -4, 6 -5^:73i— 4 . 6 ->?-b Ha- 1 , 2,
105
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4-hU7i^>-3 (2fi)
iH-NMR (400MHz, CDCI3); 5 (ppm) 4.92 (s, 2H), 7.22-7.27 (m, 2H), 7.39-7.47
(m, 8H), 7.62-7.65 (m. IH), 7.67-7.70 (m. IH), 7.72-7.75 <m, 2H).
^JS«?91 13
4- (2-:/D^r7x-;i/) -2, 6 4, 5-i?b:HD-l, 2,
iH-NMR (400MHz, CDQg); a (ppm) 4.67 (d, J=15.4 Hz, IH), 4.94 (d, J=15.4
Hz, IH), 7.21-7.31 (m, 3H), 7.36-7.46 (m, 6H), 7.49 (dd. J=8.0 Hz, 1.6 Hz, IH),
7.67 -7.71 (m, 2H), 7.73-7.77 (m, 2H).
ESI-Mass; 406 [M*+H]
HJSM 114
2- (2-':fu=Ey3L=L)i') -4- (2-:/DqE:7 3i— ;u) -6-:7x— ;i'-4.
5- v'tFD-l. 2, 4-hUT>^>-3 (2H) -:^>
^H-NMR (400MHz, CDCi^; 6 (ppm) 4.74(d, J=15.6 Hz, IH). 5.44 (d, J=16.6
Hz, IH), 6.78-6.82 (m, IH), 6.95-6.98 (m, IH), 7.12-7.30 (m, 3H), 7.38-7.53 (m,
4H), 7.59-7.74 (m, 3H), 8.54-8.58 (m, IH).
ESI-Mass; 486[M'+H]
mmm 115
4- (2->^n^:7x-;U) -6-"(2-^h^>':7a:-;i/) -2->'x-;V-4,
5- v'tHn-l, 2. 4-hUTi^>-3 (2fJ) -:^>
^H-NMR (400MHz. CDCI3); 6 (ppm) 3.82 <s, 3H), 4.55-4.82 (m, 2H). 6.88-6.98
(m, IH), 7.04 (t, J=7.6 Hz, IH), 7.13-7.27 (m, 3H), 7.32-7.41 (m, 3H), 7.45 <td,
J=7.8 Hz, 1.6 Hz, IH), 7.61-7.71 (m, 3H), 7.76 (dd, J=7.6 Hz, 1.6 Hz. IH).
ESI-Mass; 436[M*+H]
mM^i 116
2- (2.-yp^:7x-;u) -4- (2. h^>':7i-;i/) -6- (2-
^h^5^:7x-;i') -4. 5-v^tHn-l. 2. 4-h'J7-:^>-3 (2fJ) -
106
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^H-NMR (400MHz, CDCI3); d (ppm) 3.75 (s, 6H). 3.82 (s, 3H). 4.70 (s, 2H),
6.80 (dd. J=9.0 Hz, 3.0 Hz. IH), 6.87 (d, J=8.8 Hz, IH), 6.89 (d, J=8.4 Hz, IH),
6.96 (d, J=2.8 Hz, IH), 7.00 (td, J=7.4Hz, 0.4 Hz, IH), 7.17-7.20 (m, IH), 7.35-
7.40 (m, 2H), 7.64 (dd, J=4.8 Hz, 1.6 Hz, IH), 7.66 (dd, J=4.8 Hz, 1.6 Hz, IH),
7.73 (dd, J=7.6 Hz, 1.6 Hz, IH).
mnm 117
4_ (2, 5-z^>^h^i^yj^=^J^) -6- (2-;< h^->:7x-;i/) -2-7ac
-;W-4, 5-5^tHP-l, 2. 4-hUT>^>-3 (2H) -:r>
iH-NMR (400MHz. CDCi^; d (ppm) 3.74 (s. 8H), 3.76 (s, 3H), 3.81 (s, 3H),
4.66 (s, 2H), 6.83 (dd, J= 9.0 Hz, 3.0 Hz, IH), 6.86-6.94 (m, 3H), 7.03 Xt, J=7.6 Hz,
IH), 7.17 (t. J=7.4 Hz, IH), 7.32-7.41 (m, 3H), 7.67-7.71 (m, 2B), 7.75 (dd, J=7.6
Hz, 1-6 Hz, IH).
ESI-Mass; 418 [M*+H]
H WJ 118
2- (2-:/D^:7acn;l/) -6- (2-tfUi?;W -4- (2-tf«J>^;i') -4.
5-v?t:Kn-l. 2. 4->'JT>^>-3 (2J=J) -:^>
MtB^sg^ 9 2 \z^m(D:&mzm\:^xmmit^m^^^vrco
»H-N]VIR (400MHz, CDCI3); 6 (ppm) 5.16 (m, IH), 6.25-5.51 (m, IH), 7.06-
7.09 (m, IH), 7.27-7.32 (m. IH), 7.37-7.52 (m, 2H), 7:59-7.74 (m, 4H), 8.03 (d.
J=8.4Hz, IH), 8.08-8.11 (m, IH), 8.46-8.49 (m, IH), 8.63-8.66 (m, IH).
ESI-Mass; .4081M*+H1
lim^^a 119
2-:7:i:-;U-4-:7x-;l^-6- (2-t!U5>'JW -4. S-v'fcHD-l.
2, 4-hUTi/>-3 (2H)
119-1) N-^ h=^S/:*'JW2j^->>l--N-:7 3i:::;Pi/U>'>
N-:7x-;i/i^U'» (7. 2g) ^t-7*5^;w^5^;wx-7^;i' (i20mi)
t^«?b, iN7i(.mti-h^j^2^7mm (losmi) ^iQAfc. ot:ici^^b. Sfe
iy<mw\yfs~f)^^^^^^^>^^J^ (6ml) *?STU:fc^> ^iaicT— iifeiii^L
107
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3g) x-mmv. m-BmBo^^mit^^ o. ig. 92%)
^H-NMR (400MHz, CDCI3); «5 (ppm) 3.27 (brs, 3H), 4.39 (m, 2H), 7.S4-7.39 <m,
5H)-
1 1 9-2) N-pt h:^5y;^3;i.j}^-;i/-N-yx-;i'Tsy-2-x^y-;v
iq-:^\.^i^:fy)V:^-)V-N-yx.=-)V^^)i^> (3 9 5mg) SrilTK^h^b
]iuy^> (5 0ml) izmmi^. CCldJ^U ^^^ffi^T> 1. OMJ}?^>
iip^^>:|g-^-j$5^h^t l?D7^>^*0t(2. 4ml)^tBTbfco Ot)
(3T2PtPBm#L.7t^fc, 1. 0M3i^^>-7^ h^t Hci:7^>^-&'«C7^h^t:Fci
y^>mm(.2. 4m\) ^$e.lC?«Tbfco JKDitf^SS^OMU. 0'CJc:X4
B#P^it*^L/fcO-^. p^rJ'/— ;W (4 Dm 1 ) ^?STUT. j^iSlCT 2 :«-PBl^^bfc
^BETifii^bfe. @^mx5^;i/S:ljn;^. tsja^i^TK^^ b U atK^^t?^^.
(4 2 Omg. ^SW)
^H-NMR (400MHz, CDCI3); 6 (ppm) 3.68 (brs, 3H), 3.76 (t, SH), 3.83 (dt, 2H),
7.15-7.89 (m, 5H).
119-3) N-pt h^->;i!3;i'3}^x;p-N-:7xx;i/-T^yT-fe:hT;i^7'-t H
N_;^l.:^>>:^3;i,;i?-;i.-N--7xX;i.Tay-2-X^y-;V' (42 Omg)
S:>^;'^5^;U7.;P3j>^>'K (13ml) Jc^^U hUx^;i/Ta> (5ml) ^SO
^7KSSm:M- U ':7AT'^^bfco ^^^J^^:S^^> MJET^^bfco
>j*y;p*7Ai^D-7hi^^7>f— (^=^ij->-i^S^x5^;i'i^) -^^Mb.
^(DUmit^m (1 9 Img, 4 6%) .^ntZo
^H-NMR (400MHz, CDCl^; 6 (ppm) 3.72 (s, 3H), 4.40 (s, 2H), 7.24-7.39 .(m,
108
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5H). 9.70 (s, IH).
119-4) N-73:-ji/-2- (N''-7ji-;i^-n«-^
N-^ h^5/*>3i^-;U-N-:7x-;V'75/T-fehT;i'5^t F (S 0 Omg)
^jL^y-)V (2 0ml) tc^^b, 7x-;PtK^5^> (2 8 Omg) &JlP;^>
eTetrahedronVol. 52, p661-668. 19960:&fel::=eev^. ^^^^^(Dnmit^m ( 1
5 8mg) ^^ti.
^H-NMR (400MHz. CDCI3); fi(ppm) 3.75 (s. 3H), 4.79 (s, 2H), 6.85 (d, 2H).
7.22-7.38 (m, 8H), 7.68 (s, IH).
119-5) (Z) -2'- (N-:7acZ:;U-N-p^ b#>'*Jl'3|?— "
2 - tf ij S 5^ > :7 X t H ^ \/ >
N_37 3.-;V_2- (N r7x— ;l'-N''-;^ h=¥v':^J>'V'i^— >>^TS/) X^>
t l«^yy-f;W:?^a^H (1 5 8mg) $r:^->U> (lOml) tC^^U 2-bU
>'Jl'-7;i/^5^;i'7.:$'>::i;i't^'J5>?> (24 1mg) h^^X h «J 73l-
;^:1^7.7^ W'^^v^'^^ (2 5mg) tBOitm (5mg) ^iP;^> ^^^H^T
i^a©^^^b^«^ (3 7mg> 2 3%) :^#fco
^H-NMR (400MHz, CDCI3) ; 6 (ppm) 3.73 (s, 3H), 6.10 (s, 7.01-7.11 (m,
2H), 7.15-7.20 (m. 2H). 7.25-7.30 (m. 3H), 7.35-7.39 (m, 4ED, 8.€1 (d, 2H), 13.30 (s,
IH).
119-6) (E) -2'- iN-yai=.)U-N-^h^i^:^)^^—}^7^y^ ~
2 - T-fe5";i' tf' J 5 >^ > :7 X x;i/ k H ^ V >
(Z) -2'- (N-7xx;v-N-^h^v:*7;W3}?x;i/Tsy) -2-T-t5^
;l'tfUS>'>:7a:.XJl'kK^V> (5mg):<Sr0'CtCT4N4g^-ilFMX5^;KO. 5
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mg) *#fco
>H-NMR (400MH2, CBCl^; 6 (ppm) 3.74 (s, 3H), 5.28 (s, 2H), 6.95 (t, IH),
7.06-7.08 (m, 2H), 7.16-7.21 (m, 3H), 7.26-7.30 (m, 3H), 7.41-7.44 (m. 2H), 8.49 (d,
2H), 10.45 (s, IH).
119-7) 2-7xn;i/-4-73i— ;i'-6- (2-t!US>?;W) -4. 5->?
tHo-1. 2. 4-hU7i^>-3 (2iJ)
(E) -2'- (N-7x::i;P-N-^ h=^S^:d;i/:^?-;i^TSy) -2-Tiz5^
;i^t°'J5>'>:7ai-;i/t H^V'V (5mg)^X^y — (Sm l ) iC^^U, 0*0
{wTTJ-hU-^AX^^^-h (1. Img) ^Jin^. ^^gJCTlBtraiSi^bfco 11
^^y-W^m:r.^)\^m) T^ISU. ^fe^^C^^^-ffc^^lfeJ (2mg) Sr#fc.
^H-NMR (400MHz, CDCI3) ; 6 (ppm) 5.12 (s, 2H), 7.25-7.30 <in, 2H), 7.32 (t. IH),
7.40-7.47 (m. 4H), 7.51-7.57 (m, 4H), 8.85 (d, 2H).
MIBHSS^SJ 8 5 tc2pCT|IJ£^3J 1 2 0 73M 1 2 6 O^M'ffc-&#l^-&*£Ufc.
12 0
2- (2->^O^r7xX;l') -4- (4-H7aiX;i/) -€- (2-tfUS?;V) -
4, S-v'tFO-l, 2, 4-hUT>'>-3 (2/i) -:t>
^H-NMR (400MHz, CDCI3); 5 (ppm) 5.20 (brs, 2H), 7.19-7.75 <m, 15H). 8.11 (d,
IH), 8.57-8.59 (m, IH).
Hiffi^SJ 12 1
2- (.2-:fU^y:jL-)V) -4-.(3-XhD:7acn;i/) -6- (a-tfus^^w
-4. 5 -i^hFn-l. 2. 4-hU7>'>-3 ii)
110
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"^H-NMR (400MHz. CDClg) ; 6 (ppm) 5.23(brs, 2H), 7.22-7.35 (m, 2H), 7.47 <td,
IH), 7.55 (t, IH), 7.60 (dd. IH), 7.70-7.78 (m, 2H), 7.91 (dd, IH), 8.08-8.12 (m,
2H), 8.38 (t. IH). 8.60 (m, IH).
ESI-Mass; 452[lvr+H]
^»J12 2
2- (2-^a^I7ai-;0 -4- (4-y;l':^P:7-ii::i;i/) -6-
-4, 5-i?tHa-l, 2. 4-hUTe^>-3 (2H) -:^>
^H-NMR (400MHz. CDCla); 5 (ppm) 5.12 (brs. 2H). 7.06-7.11 (m. 2H). 7.24-7.29
(m, IH). 7.30 (ddd, IH), 7.41-7.49 (m, 3H), 7.60 (dd, IH), 7.68-7.75 (m, 2H), 8.10
(d, IH), 8.56-8.58 (m, IH).
^Sg^Jl 2 3
2- i2-^u^yx.=i)\^) -4- (3-3j^ji/^;i':7 3i~;W -6- (2-t!U>?
}U) -4. S-e^tHP-l, 2. 4-hUTS^>-3 (2H)
^H-NMR (400MHz, CDCI3) ; 6 (ppm) 5.20 (brs, 2H), 7.18-7.34 (m, 2H), 7.46 Xtd,
IH), 7.57 (t, IH), 7.iB3 (dd, IH), 7.56-7.70 (m. 3H), 7.83 (ddd, IH), 8.02 (t. IH).
8.11 (dt, IH). 8.58-8.59 (mi, IH), 10.03 (s, IH).
*JS«fiJ 12 4
2- (2-:/a^73in;p) -4- (3-h;i^-r;w) -6- (2-tru>^;w) -4.
5-S^tHn-l. 2, 4-bUTS?>-3 (2H) -:^>
^H-NMR (400MHz. CDCla) ; 6 (ppm) 2.37 (s, 3H), 5.13 (brs, 2H), 7.04 (t, IH),
7.23-7.33 (m,.5H), 7.44 (td, IH). 7.62 (dd, IH), 7.68-7.70 (m. IH), 7.73 (dd, IH).
8.10 (d, IH), 8.56-8.58 (m, IH).
||Jg{«Jl2 5
2- (2 -yD^:7a:-;i/) -4- (4 -^:t ^ h^i^^ 3^=^)1") -6" (2-t!
'Jv^;W -4. S-e^tHo-l. 2. 4-hUTi^>-3 (2ii) -:^>
^H-NMR (400MHz, CDCI3) ; 6 (ppm) 2.50 (s. 3H). 5.13 (brs, 2H), 7.26-7.32 (m,
3H), 7.42-7.47 (m, 2H), 7.53-7.57 (m. IH). 7.63 (dd, IH). 7.70-7.76 <m, 3H), 8.11
(d, IH), 8.57-8.60 (m, IH).
Ill
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mmm 126
2- (2->^o^::7x:z;i') -4- (2-^7DntfUi^>-5— r;i') -6- (2
-tf'Ji^JU) -4. 5--:^tFD-l. 2. 4-hU7i^>-3 (2if) -:^>
^H-NMR (400MHz, CDGI3) ; 6 (ppm) 5.18 (brs, 2H), 6.99-8.11 (m, lOH), 8.56-
8.60 (m, IH).
IIJiS««Jl2 7
2- (2-v'Ty ^x-jp) -4- (3--hD7x^;w -6- (2-tfue?;0
-4. S-v'tHD-l, 2, 4-h'JTe^>-3 (2/i) -:t>
Wia^lJS'^s 7{z2pi;, 2- (2-::^P^:7x-;l') -4- (3--hn7x~
-6- (2-t:U5^;i') -4, 5->^tHD-l. 2. 4-bUTi?>-3 (2
^H-NMR (400MHz, CDCI3) ; 6 (ppm) 5.24 (brs, 2H), 7.86 (ddd, IH), 7.46 (td,
IH), 7.59 (t, IH). 7.69-7.81 (m, 4H). 7.90 (ddd, IH), 8,12 (ddd, IH), 8.20 <dt, IH),
8.38 (t, IH), 8.60 (ddd, IH).
ESI-Mass; 399IM*+H]
rnmm 123
2_ (2->'Ty >'x-;W -4- (3-TSy7x:::i;W - 6 - (2 -t!U i?;!')
-4. 5->^tFo-l. 2. 4-bUTi?>-3 (2J^)
2- (2->'Ty:7xn;i.) -4- ( 3 -r^ h n^x^r)!.) -6- (2-t!U>?
;W -4, S-v'tFa-l, 2. 4 - hUT5^>-3 (2ii) -:^> (1 5mg)
^^^y—)]^ (3ml) 1 0 v'C^A-;^?— (-^TKffi) (2
Img) =&tnJ^x 7K^^ffl^T4I^FBmiafcTmi^Lfc. /'?7>^':7A-:^-4^>«&5f5
-7^_ (^4-it>-i^^x5^;i/?^) TJitisu, m^i^^<Dmmit^^ d 3mg)
^H-NME (400MHz, CDClj); 6 (ppm) 3.72 (brs, 2H), 5.13 (s, 2H), 6.58 (ddd, IH),
6.82-6.85 (m, 2H), 7.19 (t, IH), 7.32 (ddd, IH), 7.40 (td, IH), 7.67 (td, IH), 7.73-
7.78 (m, 3H), 8.20 (dt, IH), 8.58 (ddd, IH).
112
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ESI-Mass 369 [M^+H]
mmm 12 9",
2_ (2-^no7airi;W -4-:73i-;i/-6- (2-fc:'J5>^JW -4, 5-
»H-NMR (400MHz, CDCI3) ; 6 (ppm) 5.18(brs. 2H), 7.25(tt, IH). 7.28-7.44(m,
5H), 7.47-7.51(m, 3H), 7.65(dd, IH), 8.84(d, 2H).
ESI-Mass; 364 [M*+H]
113
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126
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127
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-2. 3. 4. 4 a-xh^t:FD-5ff- (!> [4, 3-c] tf
ijy->->-3-:t>. 2- <2-iyTyy3L=-)V) -4- (S-b^Ui^;!/) -2.
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2- (2-:rD^7x3l ;W -4- (2-fcHn^^>'73i^;i') -6- (2
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128
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129
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5- vtHP-l. 2, 4-hU7>'>-3 (2Jy) -:^>. 2- (2-7*0^:7
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165
INTERNATIONAL SEARCH REPORT
Intetnational application No.
PCT/JPOl/08058
A. CLASSJFpVT^^^^^^^ ^^^^^^^ ^^^^^^^ ^^^^^^^^
403/14/409/14, 417/04, 253/06, A61K31/501, 31/50, 31/5025, 31/506, 31/53,
31/5377, A61P43/00, 25/00, 9/10, 25/28, 25/16. 25/14, 21/04. 25/08, 25/02. ^S/06,
According to IntemaSona^ ktenf ^^Jsifi^on^(lP(j)^^^ both national classification and B>C ^
B. FIELDS SEARCHED
Minimum documentation searched (classification systrai followed by classificabon S3to1>o1s) 405/14
Int.Cl^ C07D237/04, 401/04, 237/14, 401/06, 409/04, 491/052, 491/048, 401/14, Z^%lZ'
403/14, 409/14, 417/04, 253/06, A61i31/501, 31/SO, 31/S025, 31/506, 31/53, 31/5377
Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
Electronic data base consuUed during the international search (name of data base and, where practicable, search tenns used)
CA (STN) , REGISTRY (STN) , WPIDS (STN)
C. DOCUMENTS CONSIDERED TO BE RELEVANT
Category*
Citation of document, with indication, where appropriate, of the relevant passages
US 5426106 A (Merck Sharp & Dohme Limited) ,
20 June, 1995 (20.06.95),
the whole document
& GB 2265372 A
WO 00/50408 A (Kowa Company, Ltd.),
31 August, 2000 (31.08,00),
Claims
& JP. 2000247959 A
JP 2000-119257 A (Nihon Nohyaku Co., Ltd.),
25 April, 2000 (25.04.00),
Claims
& WO 00/09488 A
WO 99/44995 A (Kowa Company, Ltd.),
10 September, 1999 (10.09.99),
Claims; working example 70 et al.
& EP 1061077 A
Relevant to claim No.
1-55,58,59
1-9,13,
18-20,40
1-13,
18-20,40
1-9,12,13,
18-20,40-50
Further documents are listed in the continuation of Box C. [U See patent fanaily annex.
«o-
Special categories of cited documents:
document defining the general state of the art which is not
considered to be of particular relevance
earlier document but published on or after the intemational filing
date
document which may throw doubts on priority claim(s) or which is
cited to establish the publication date of another citation or otiier
special reason (as specified)
document referring to an oral disclosure, use, exhibition or other
means
document published prior to the international filing date but later
than the priority date claimed
•T' later document pubUshed after the intemational filing date or
priority date and not in conflict with the application but cited to
understand the principle or theory underlying the invention
"X" document of particular relevance; the claimed invention cannot be
considered novel or cannot be considered to involve an inventive
step when the document is taken alone
*V document of particular relevance; the claimed invention cannot be
considered to involve an inventive step when the document is
combined with one or more otiier such documents, such
combination being obvious to a pereon skilled in the art
document member of the same patent family
Date of the actual completion of the intemational search
05 October, 2001 (05.10.01)
Name and mailing address of the ISA/
Japanese Patent Of f ioe
Facsimile No.
Pate of mailing of the intemational search report
23 October, 2001 (23.10.01)
Authorized officer
Telephone No.
Form PCT/ISA/210 (second sheet) (July 1992)
INTERNATIONAL SEARCH REPORT
Inlemational application No.
PCT/JPOl/ 0-8058
C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT
Category*
Citation of document, with indication, where appropriate, of the relevant passages
Relevant to claim No.
X
jp 8-225540 A (Rohm and Haas Company) ,
03 Septemtfer/ 1996 (03.09.96),
Claims; Working example 67 et al.
Sc EP 711759 A
1^9,11-13,
18-20,40
X
JP 5-221992 A (Dr. Karl Thomae GmbH),
31 August/ 1993 (31.08.93),
Claims; chemical compound (18), et al-
& EP 537696 A .
1-9,13,
18-20,40
Fonn PCT/ISA/210 (continuation of second sheet) (July 1992)
INTERNATIONAL SEARCH REPORT
International application No.
PCT/JPOl/08058
Box I Observations where certain claims were found unsearchable (Continuation of item 1 of first sheet)
This international search report has not been established in respect of certain claims under Article 17(2Xa) for the following reasons:
1. S Claims Nos.: 56,57
because they relate to subject matter not reqmred to be searched by this Authority, namely:
The inventions of claims 56 and 57 fall under the category of ^methods
for treatment of the human body by surgery or therapy" as provided for in
Rule 39.1{iv) of the Regulations tinder the POT,
2. 13 Claims Nos.: 1-21
because diey relate to parts of the international application that do not conq>ly with the prescribed requirements to such an
extent that no meaningful international search can be carried out, specifically:
The inventions of claims 1 and 19 include extremely many compounds
with various compounds excluded, so that the structural features of the
compounds of the inventions are unclear.
Namely, the inventions of claims 1 and 19 are unclear. Further, the
same applies to the inventions of claims 2-18, 20 and 21 referring to<:laira
1 or 19.
Thus, claims 1-21 fail to comply with the prescribed requirements
to such an extent that a meaningful search could not be carried out.
In this international search report , prior art search has been carried
out on the basis of the compoxmds disclosed specif i<3ally in the description.
3. n Claims Nos.: ^ a/ \
becaxise tiicy are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).
Box n Observations where unity of invention is lacking (Continuation of item 2 of first sheet)
This International Searching Authority found multiple inventions in this international application, as follows:
1 . As all required additional search fees were timely paid by die applicant, this intmational search report covers all searchable
claims.
2. Q As all searchable claims could be searched without effort justifying an additional fee, this Authority did not invite payment
of any additional fee.
3. Q As only some of the required additional search fees were timely paid by the applicant, this mtemational search report covers
only those claims for which fees were paid, specifically claims Nos.:
4. []] No required additional search fees were timely paid by the applicant Consequently, this international
search report is restricted to die invention first mentioned in the claims; it is covered by claims Nos.:
Remark on Protest \Z} additional search fees were accompanied by the applicant's protest
I I No protest accompanied the payment of additional search fees.
Fonn PCT/rSA/210 (continuation of first sheet (1)) (July 1992)
a^ai«#^ PCT/J PO l/0-8 0« 8
a: ^?S©Jgi-.5:»lfo5>?i (ffl^#fF55« (I PC) )
Int cl' C07D2 3 7/'04, 401/04, 237/1 4, 40 1/06, 4O9/04, 4 9 1/0 5
2, 491/048, 401/14, 405/14, 403/14. 409/14, 41 7/04, 25 3/06, A
61K3 1/50 1. 3 1/50, 3 1/502 5, 3 1/506, 3 1/5 3, 3 1/5 3 7 7,
B.
fs^t:no±Mc'hmm^ mwMff^^m ( i p o )
Int cl' C07D23 7/04, 40 1/04, 2 37/1 4, 40 1/06, 4 O 9/0 4, 4 9 1 /O 5
2 49 1/048, 40 1/14, 405/14, 4 0 3/14. 409/14. 4 1 7/04. 253/06, A
61X3 1/50 1. 3 1/50. 3 1/502 5. 3 1/506, 3 1/5 3, 3 1/5377
Hissa^-eieffi ^"<— ^ i?^— ;^«>ife», fjasfcffifli ufcffis)
CA (STN) , REG I STRY (STN) , WP IDS (STN)
us 5 4 2 6 10 6
6^. 1 9 9 5 (2 0
5 3 7 2 A
A (MERCK SHARP & DOHME LIMITED) 2 O .
06. 9 5):S:ifc^**: & GB 22 6
X
WO 00/5 0408 A (^?0^^^l±) 3 1. 8^. 2 0 0
0 (3 1. 0 8. 0 0) m^(Dmm & jp 20002479
59 A
JP 2000-119257 A {P^^mmm^^^ 2 S . 4
M. 20 00 (2 5. 0 4, 0 0) #ffft^O®H & WO
0 0/0 9 4 8 8 A
1-55,68,-59
I- 9 , 13, 18-
.20. 40
1-13. 18-20
.40
r&j m—''^^>'h7TS.i)'-SM
@§gSSSSr^TLfcB ,^ ^,
0 5. 10. 0 1
BEgisifi^^o^asa 23 1 0 C
)l
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